Carole Oddoux, Ph.D.

The impact of Converso Jews on the genomes of modern Latin Americans
Velez, C; Palamara, P F; Guevara-Aguirre, J; Hao, L; Karafet, T; Guevara-Aguirre, M; Pearlman, A; Oddoux, C; Hammer, M; Burns, E; Pe'er, I; Atzmon, G; Ostrer, H
2012 Feb;131(2):251-263, Human genetics
Modern day Latin America resulted from the encounter of Europeans with the indigenous peoples of the Americas in 1492, followed by waves of migration from Europe and Africa. As a result, the genomic structure of present day Latin Americans was determined both by the genetic structure of the founding populations and the numbers of migrants from these different populations. Here, we analyzed DNA collected from two well-established communities in Colorado (33 unrelated individuals) and Ecuador (20 unrelated individuals) with a measurable prevalence of the BRCA1 c.185delAG and the GHR c.E180 mutations, respectively, using Affymetrix Genome-wide Human SNP 6.0 arrays to identify their ancestry. These mutations are thought to have been brought to these communities by Sephardic Jewish progenitors. Principal component analysis and clustering methods were employed to determine the genome-wide patterns of continental ancestry within both populations using single nucleotide polymorphisms, complemented by determination of Y-chromosomal and mitochondrial DNA haplotypes. When examining the presumed European component of these two communities, we demonstrate enrichment for Sephardic Jewish ancestry not only for these mutations, but also for other segments as well. Although comparison of both groups to a reference Hispanic/Latino population of Mexicans demonstrated proximity and similarity to other modern day communities derived from a European and Native American two-way admixture, identity-by-descent and Y-chromosome mapping demonstrated signatures of Sephardim in both communities. These findings are consistent with historical accounts of Jewish migration from the realms that comprise modern Spain and Portugal during the Age of Discovery. More importantly, they provide a rationale for the occurrence of mutations typically associated with the Jewish Diaspora in Latin American communities
— id: 149942, year: 2012, vol: 131, page: 251, stat: Journal Article,

Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk
Kaklamani, Virginia; Yi, Nengjun; Zhang, Kui; Sadim, Maureen; Offit, Kenneth; Oddoux, Carole; Ostrer, Harry; Mantzoros, Christos; Pasche, Boris
2011 Sep;60(9):1234-1243, Metabolism clinical & experimental
Studies have linked prostate cancer risk with insulin resistance and obesity. Circulating levels of adiponectin, a protein involved in insulin resistance and obesity, have been associated with prostate cancer risk. We studied the association of prostate cancer risk with haplotype tagging single nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) chosen based on their functional relevance or association with other types of cancer. DNA samples from 465 cases and 441 healthy volunteers from New York City were genotyped for ADIPOQ rs266729, rs822395, rs822396, rs1501299, and rs2241766 SNPs and ADIPOR1 rs12733285, rs1342387, rs7539542, rs2232853, and rs10920531 SNPs. We performed both single- and multiple-SNP analyses. We found that rs12733285, rs7539452, rs266729, rs822395, rs822396, and rs1501299 were significantly associated with prostate cancer risk. Haplotype analysis confirmed these results and identified 5 ADIPOQ 4-SNP haplotypes and 1 ADIPOR1 2-SNP haplotype tightly associated with prostate cancer risk. Importantly, 2 ADIPOQ SNPs, rs266729 and rs1501299, have been previously associated with colon and breast cancer risk, respectively, in the same direction as in this study. These findings suggest that variants of the adiponectin pathway may be associated with susceptibility to various forms of common cancers and warrant validation studies
— id: 137960, year: 2011, vol: 60, page: 1234, stat: Journal Article,

Genetic marker polymorphisms on chromosome 8q24 and prostate cancer in the Dutch population: DG8S737 may not be the causative variant
Zeegers, Maurice P; Khan, Humera S; Schouten, Leo J; van Dijk, Boukje A C; Goldbohm, R Alexandra; Schalken, Jack; Shajahan, Shahin; Pearlman, Alexander; Oddoux, Carole; van den Brandt, Piet A; Ostrer, Harry
2011 Jan;19(1):118-120, European journal of human genetics
Prostate cancer is the most commonly diagnosed cancer in men in Europe and Northern America. Genome-wide association studies (GWAS) have detected an association with markers on chromosome 8q24. Allele -8 of microsatellite DG8S737 with 22 repeats and allele A of the single-nucleotide polymorphism (SNP) rs1447295 have been found to be significantly associated with prostate cancer. As GWAS are subjected to type 1 error, confirmation studies are required to validate the results. Here, we analysed the same markers in 277 cases and 282 controls from the Netherlands using a nested case-control study. Incident prostate cancer cases and controls selected were identified in the population of the Netherlands Cohort Study. We also investigated clinical features of the disease by stratifying by tumour stage. We did not replicate the association with the SNP rs1447295-A allele (P=0.10), although the effect estimate was in the same direction as previous studies (odds ratio (OR), 1.38). Interestingly a statistically significant decreased risk was observed for DG8S737 allele -8 (OR, 0.62; P=0.03). The apparent protective effect of the DG8S737 -8 allele observed in this study contrasts with the Amundadottir study. This suggests that DG8S737 and rs1447295 might be tightly linked markers flanking the actual causative variant and that there may be potentially more than one high-risk haplotype present in the Caucasian population. This short report highlights the importance of validation, although further confirmation is still needed
— id: 134189, year: 2011, vol: 19, page: 118, stat: Journal Article,

Abraham's children in the genome era: major Jewish diaspora populations comprise distinct genetic clusters with shared Middle Eastern Ancestry
Atzmon, Gil; Hao, Li; Pe'er, Itsik; Velez, Christopher; Pearlman, Alexander; Palamara, Pier Francesco; Morrow, Bernice; Friedman, Eitan; Oddoux, Carole; Burns, Edward; Ostrer, Harry
2010 Jun 11;86(6):850-859, American journal of human genetics
For more than a century, Jews and non-Jews alike have tried to define the relatedness of contemporary Jewish people. Previous genetic studies of blood group and serum markers suggested that Jewish groups had Middle Eastern origin with greater genetic similarity between paired Jewish populations. However, these and successor studies of monoallelic Y chromosomal and mitochondrial genetic markers did not resolve the issues of within and between-group Jewish genetic identity. Here, genome-wide analysis of seven Jewish groups (Iranian, Iraqi, Syrian, Italian, Turkish, Greek, and Ashkenazi) and comparison with non-Jewish groups demonstrated distinctive Jewish population clusters, each with shared Middle Eastern ancestry, proximity to contemporary Middle Eastern populations, and variable degrees of European and North African admixture. Two major groups were identified by principal component, phylogenetic, and identity by descent (IBD) analysis: Middle Eastern Jews and European/Syrian Jews. The IBD segment sharing and the proximity of European Jews to each other and to southern European populations suggested similar origins for European Jewry and refuted large-scale genetic contributions of Central and Eastern European and Slavic populations to the formation of Ashkenazi Jewry. Rapid decay of IBD in Ashkenazi Jewish genomes was consistent with a severe bottleneck followed by large expansion, such as occurred with the so-called demographic miracle of population expansion from 50,000 people at the beginning of the 15th century to 5,000,000 people at the beginning of the 19th century. Thus, this study demonstrates that European/Syrian and Middle Eastern Jews represent a series of geographical isolates or clusters woven together by shared IBD genetic threads
— id: 133499, year: 2010, vol: 86, page: 850, stat: Journal Article,

Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination
Pearlman, Alexander; Loke, Johnny; Le Caignec, Cedric; White, Stefan; Chin, Lisa; Friedman, Andrew; Warr, Nicholas; Willan, John; Brauer, David; Farmer, Charles; Brooks, Eric; Oddoux, Carole; Riley, Bridget; Shajahan, Shahin; Camerino, Giovanna; Homfray, Tessa; Crosby, Andrew H; Couper, Jenny; David, Albert; Greenfield, Andy; Sinclair, Andrew; Ostrer, Harry
2010 Dec 10;87(6):898-904, American journal of human genetics
Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination
— id: 115279, year: 2010, vol: 87, page: 898, stat: Journal Article,

Copy number and gene expression differences between African American and Caucasian American prostate cancer
Rose, Amy E; Satagopan, Jaya M; Oddoux, Carole; Zhou, Qin; Xu, Ruliang; Olshen, Adam B; Yu, Jessie Z; Dash, Atreya; Jean-Gilles, Jerome; Reuter, Victor; Gerald, William L; Lee, Peng; Osman, Iman
2010 ;8(1):70-70, Journal of translational medicine
ABSTRACT: BACKGROUND: The goal of our study was to investigate the molecular underpinnings associated with the relatively aggressive clinical behavior of prostate cancer (PCa) in African American (AA) compared to Caucasian American (CA) patients using a genome-wide approach. METHODS: AA and CA patients treated with radical prostatectomy (RP) were frequency matched for age at RP, Gleason grade, and tumor stage. Array-CGH (BAC SpectralChip2600) was used to identify genomic regions with significantly different DNA copy number between the groups. Gene expression profiling of the same set of tumors was also evaluated using Affymetrix HG-U133 Plus 2.0 arrays. Concordance between copy number alteration and gene expression was examined. A second aCGH analysis was performed in a larger validation cohort using an oligo-based platform (Agilent 244K). RESULTS: BAC-based array identified 27 chromosomal regions with significantly different copy number changes between the AA and CA tumors in the first cohort (Fisher's exact test, P < 0.05). Copy number alterations in these 27 regions were also significantly associated with gene expression changes. aCGH performed in a larger, independent cohort of AA and CA tumors validated 4 of the 27 (15%) most significantly altered regions from the initial analysis (3q26, 5p15-p14, 14q32, and 16p11). Functional annotation of overlapping genes within the 4 validated regions of AA/CA DNA copy number changes revealed significant enrichment of genes related to immune response. CONCLUSIONS: Our data reveal molecular alterations at the level of gene expression and DNA copy number that are specific to African American and Caucasian prostate cancer and may be related to underlying differences in immune response
— id: 111525, year: 2010, vol: 8, page: 70, stat: Journal Article,

MDM2 Expression and Regulation in Prostate Cancer Racial Disparity
Wang, Guimin; Firoz, Elnaz F; Rose, Amy; Blochin, Elen; Christos, Paul; Pollens, Danuta; Mazumdar, Madhu; Gerald, William; Oddoux, Carole; Lee, Peng; Osman, Iman
2009 ;2(4):353-360, International journal of clinical & experimental pathology
MDM2 is a key negative regulator of tumor suppressor p53. A single nucleotide polymorphism in the MDM2 promoter, SNP309, enhances transcriptional activation of MDM2 and has been associated with early onset of several types of cancer. In this study, we attempted to determine if the MDM2 SNP309 polymorphism plays a role in the aggressive phenotype seen in African American (AA) prostate cancer by examining the association between MDM2 SNP309 and MDM2 protein levels in prostate cancer (PCa) patients of different racial backgrounds. Prospectively enrolled PCa patients (AA=51, CA=50) were evaluated for MDM2 SNP309 and MDM2 protein expression. MDM2 overexpression, defined as >10% of tumor cells in three tissue cores, was assessed using immunohistochemistry on tissue microarray. MDM2 protein expression was significantly greater in CA than AA patients (78% versus 45% respectively, p=0.0007). Germline DNA was analyzed by PCR-RFLP then confirmed by DNA sequencing. MDM2 SNP309 genotype frequencies did not differ significantly between AA and CA PCa patients (AA: TT 68.6%, TG 25.5%, GG 5.9%; CA: TT 62.0%, TG 20.0%, GG 18.0%; p=0.16), suggesting that the MDM2 SNP309 allele does not play a significant role in the observed overexpression
— id: 92155, year: 2009, vol: 2, page: 353, stat: Journal Article,

Hereditary Sensory and Autonomic Neuropathy IV
Axelrod, Felicia B; Gold-von Simson, Gabrielle; Oddoux, Carole
GeneReviews Seattle WA : University of Washington, 2008,
Disease characteristics. Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is characterized by congenital profound sensory loss affecting perception of pain and temperature, and absence of sweating. Secondary consequences of reduced pain perception include: oral self-mutilation (biting of tongue, lips, and buccal mucosa); fingertip biting; repeated bone fractures and joint trauma. Anhidrosis results in poor thermoregulation in hot environmental conditions and can cause recurrent febrile episodes. Although developmental milestones are usually normal to only mildly delayed, learning problems can be severe. Hyperactivity and emotional lability are common. Diagnosis/testing. Axon flare after intradermal histamine phosphate injection is absent, a finding in all HSAN types that is not specific to HSAN IV. Mutations in NTRK1 (TRKA), the only gene known to be associated with HSAN IV, are identified by sequence analysis in almost all individuals meeting HSAN IV diagnostic criteria. Management. Treatment of manifestations: prevention of self-mutilation by smoothing or extracting teeth; prevention of secondary severe or debilitating orthopedic problems by daily evaluation for early signs of unrecognized injury; control of hyperthermia with acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket; prevention of neurotrophic keratitis with tarsorrhaphy, corneal patch graft, keratoplasty, and/or scleral bandage lens. Antipsychotic and/or ADHD medications in conjunction with behavior modification as needed. Interventions for behavioral, developmental, and motor delays; educational and social support for school-age children and adolescents. Prevention of secondary complications: attention to temperature management during the perioperative period. Surveillance: annual evaluations with ophthalmology, dentistry, and orthopedics. Agents/circumstances to avoid: hot, dry climates; high-impact activities and sports; inadequate sedation in the postoperative period. Testing of relatives at risk: clarify the genetic status of at-risk infants by molecular genetic testing for the family-specific mutations in order to prevent hyperpyrexia in those who are affected. Genetic counseling. HSAN IV is inherited in an autosomal recessive manner. Uniparental disomy (UPD) has been reported. Each child of known carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the disease-causing mutations have been identified in a family
— id: 5308, year: 2008, vol: , page: ?, stat: Chapter,

Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk
Kaklamani, Virginia G; Sadim, Maureen; Hsi, Alex; Offit, Kenneth; Oddoux, Carole; Ostrer, Harry; Ahsan, Habibul; Pasche, Boris; Mantzoros, Christos
2008 May 1;68(9):3178-3184, Cancer research
Breast cancer risk is higher among obese women and women with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associated with breast cancer risk. Whether genetic variants within the adiponectin pathway are associated with breast cancer risk is unknown. To explore the association of genetic variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with breast cancer risk, we conducted a case control study of female patients with breast cancer and healthy female controls from New York City recruited between 1999 and 2004. We genotyped 733 hospital-based breast cancer cases and 839 controls for 10 haplotype-tagging single nucleotide polymorphisms (SNP) of ADIPOQ and ADIPOR1. Two ADIPOQ SNPs (rs2241766 and rs1501299), which have been associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios (OR), 1.80; 95% confidence interval (95% CI), 1.14-2.85; rs2241766*TG: OR, 0.61; 95% CI, 0.46-0.80]. One ADIPOR1 SNP (rs7539542), which modulates expression of adiponectin receptor 1 mRNA, was also associated with breast cancer risk (OR, 0.51; 95% CI, 0.28-0.92). Based on the known function of rs2241766 and rs1501299, we categorized individuals by adiponectin signaling status and found that, when compared with high signalers, intermediate signalers had a 4.16-fold increase in breast cancer risk (95% CI, 0.49-35.19), and low signalers had a 6.56-fold increase in breast cancer risk (95% CI, 0.78-54.89; P(trend) = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer
— id: 96915, year: 2008, vol: 68, page: 3178, stat: Journal Article,

Novel mutations in tyrosine kinase domain of epidermal growth factor receptor in prostate cancer
Douglas, D; Zhong, H; Ro, J; Oddoux, C; Pincus, M; Satagopan, J; Gerald, W; Schei, H; Lee, P; Osman, I
2006 JUN 20 ;24(18):244S-244S, Journal of clinical oncology
— id: 69297, year: 2006, vol: 24, page: 244S, stat: Journal Article,

Novel mutations of epidermal growth factor receptor in localized prostate cancer
Douglas, Diah A; Zhong, Hong; Ro, Jae Y; Oddoux, Carole; Berger, Aaron D; Pincus, Matthew R; Satagopan, Jaya M; Gerald, William L; Scher, Howard I; Lee, Peng; Osman, Iman
2006 ;11:2518-2525, Frontiers in biosciences
We recently demonstrated that EGFR protein overexpression is more common in African American (AA) prostate cancer patients compared to Caucasian patients. We further examine EGFR dysregulation by determining EGFR mutation status in the tyrosine kinase (TK) domain in prostate cancer patients of different ethnicity. Normal and tumor DNA from 89 radical prostatectomy cases were studied for mutations in the EGFR TK domain using genomic DNA sequencing. We identified 4 novel missense mutations in exons 19, 20 and 21 of EGFR TK domain: 3 in Koreans and 1 in Caucasian but none in AA. We also identified 5 distinct synonymous DNA sequence changes, which did not alter the encoded amino acid, in exons 20 and 21 in 31/89 (35%) patients. Interestingly, these synonymous sequence changes were not observed in normal DNA in 7(23%) patients, indicating the presence of de novo somatic mutation to a new synonymous sequence. Our data reveal that EGFR missense mutation in the TK domain occurs in localized prostate cancer. Our data also demonstrate the presence of somatic mutation to a new synonymous sequence in a subset of patients. Larger population-based studies are required to define the association between EGFR mutations and the ethnic background of patients
— id: 64213, year: 2006, vol: 11, page: 2518, stat: Journal Article,

Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk
Kaklamani, Virginia G; Baddi, Lisa; Liu, Junjian; Rosman, Diana; Phukan, Sharbani; Bradley, Ciaran; Hegarty, Chris; McDaniel, Bree; Rademaker, Alfred; Oddoux, Carole; Ostrer, Harry; Michel, Loren S; Huang, Helen; Chen, Yu; Ahsan, Habibul; Offit, Kenneth; Pasche, Boris
2005 Apr 15;65(8):3454-3461, Cancer research
There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population
— id: 61171, year: 2005, vol: 65, page: 3454, stat: Journal Article,

The frequency of GJB2 and GJB6 mutations in the New York State newborn population: feasibility of genetic screening for hearing defects
Fitzgerald, T; Duva, S; Ostrer, H; Pass, K; Oddoux, C; Ruben, R; Caggana, M
2004 Apr;65(4):338-342, Clinical genetics
In the US, approximately one in every 1000 children has hearing loss sufficiently severe to interfere with the acquisition of normal speech [Ann NY Acad Sci 630 (1991) 16]. The causes of non-syndromic hearing loss (NSHL) are known to be heterogeneous, with genetic factors accounting for 50-75%[Am J Med Genet 46 (1993) 486]. Often individuals with NSHL thought to be caused by mutations in GJB2 have only one detectable mutant allele [Am J Hum Genet 62 (1998) 792, Hum Mol Genet 6 (12) (1997) 2173]. Another gene that has been identified as a possible cause of NSHL is GJB6 that codes for the gap junction protein, connexin 30. A consecutive series of anonymous newborn dried blood specimens (n = 2089) was tested for two GJB2 mutations: (i) 35delG, a pan-ethnic mutation; and (ii) 167delT, a mutation more frequently found in individuals of Ashkenazi Jewish and Mediterranean descents. Mutation detection was validated using allele-specific oligonucleotide hybridization in single wells. Once the positive samples had been identified, the samples were pooled and retested. All positives in the individual experiment were correctly identified in the pooled experiment. The same random set of anonymous newborn dried blood specimens plus some additional samples were tested (n = 2112) for the 342-kb deletion in the GJB6 gene
— id: 44826, year: 2004, vol: 65, page: 338, stat: Journal Article,

No major association between TGFBR1*6A and prostate cancer
Kaklamani, Virginia; Baddi, Lisa; Rosman, Diana; Liu, Junjian; Ellis, Nathan; Oddoux, Carole; Ostrer, Harry; Chen, Yu; Ahsan, Habibul; Offit, Kenneth; Pasche, Boris
2004 Sep 22;5:28-28, BMC genetics
Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer
— id: 61173, year: 2004, vol: 5, page: 28, stat: Journal Article,

A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome
Ben-Yosef, Tamar; Ness, Seth L; Madeo, Anne C; Bar-Lev, Adi; Wolfman, Jessica H; Ahmed, Zubair M; Desnick, Robert J; Willner, Judith P; Avraham, Karen B; Ostrer, Harry; Oddoux, Carole; Griffith, Andrew J; Friedman, Thomas B
2003 Apr 24;348(17):1664-1670, New England journal of medicine
— id: 34762, year: 2003, vol: 348, page: 1664, stat: Journal Article,

Identification of the first non-Jewish mutation in familial Dysautonomia
Leyne, Maire; Mull, James; Gill, Sandra P; Cuajungco, Math P; Oddoux, Carole; Blumenfeld, Anat; Maayan, Channa; Gusella, James F; Axelrod, Felicia B; Slaugenhaupt, Susan A
2003 May 1;118A(4):305-308, American journal of medical genetics
Familial Dysautonomia is an autosomal recessive disease with a remarkably high carrier frequency in the Ashkenazi Jewish population. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease-causing mutations have been identified. The most common mutation, which is present on 99.5% of all FD chromosomes, is an intronic splice site mutation that results in tissue-specific skipping of exon 20. The second mutation, R696P, is a missense mutation that has been identified in 4 unrelated patients heterozygous for the major splice mutation. Interestingly, despite the fact that FD is a recessive disease, normal mRNA and protein are expressed in patient cells. To date, the diagnosis of FD has been limited to individuals of Ashkenazi Jewish descent and identification of the gene has led to widespread diagnostic and carrier testing in this population. In this report, we describe the first non-Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L. This mutation is of particular significance because it was identified in a patient who lacks one of the cardinal diagnostic criteria for the disease-pure Ashkenazi Jewish ancestry. In light of this fact, the diagnostic criteria for FD must be expanded. Furthermore, in order to ensure carrier identification in all ethnicities, this mutation must now be considered when screening for FD
— id: 34763, year: 2003, vol: 118A, page: 305, stat: Journal Article,

Genotype-phenotype correlation of hereditary sensory neuropathy type 4: Extension of the phenotype
Oddoux, C; Maayan, C; Cilio, R; Axelrod, F
2003 NOV ;73(5):550-550, American journal of human genetics
— id: 55455, year: 2003, vol: 73, page: 550, stat: Journal Article,

Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function
Kurima, Kiyoto; Peters, Linda M; Yang, Yandan; Riazuddin, Saima; Ahmed, Zubair M; Naz, Sadaf; Arnaud, Deidre; Drury, Stacy; Mo, Jianhong; Makishima, Tomoko; Ghosh, Manju; Menon, P S N; Deshmukh, Dilip; Oddoux, Carole; Ostrer, Harry; Khan, Shaheen; Riazuddin, Sheikh; Deininger, Prescott L; Hampton, Lori L; Sullivan, Susan L; Battey, James F Jr; Keats, Bronya J B; Wilcox, Edward R; Friedman, Thomas B; Griffith, Andrew J
2002 Mar;30(3):277-284, Nature genetics
Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells
— id: 34766, year: 2002, vol: 30, page: 277, stat: Journal Article,

Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers
Offit, Kenneth; Gilad, Shlomit; Paglin, Shoshana; Kolachana, Prema; Roisman, Laila C; Nafa, Khedoudja; Yeugelewitz, Vincent; Gonzales, Maria; Robson, Mark; McDermott, Deborah; Pierce, Heather Hanson; Kauff, Noah D; Einat, Paz; Jhanwar, Suresh; Satagopan, Jaya M; Oddoux, Carole; Ellis, Nathan; Skaliter, Rami; Yahalom, Joachim
2002 Dec;8(12):3813-3819, Clinical cancer research
PURPOSE: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers. EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region. RESULTS: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases
— id: 34764, year: 2002, vol: 8, page: 3813, stat: Journal Article,

SRY gene expression in the ovotestes of XX true hermaphrodites
Ortenberg, Joseph; Oddoux, Carole; Craver, Randall; McElreavey, Ken; Salas-Cortes, L; Guillen-Navarro, Encarnacion; Ostrer, Harry; Sarafoglou, Kyriakie; Clarke, Virginia; Yee, Herman
2002 Apr;167(4):1828-1831, Journal of urology
PURPOSE: The pathogenesis of 46 XX true hermaphroditism is uncertain and the role of the SRY gene in ovotestis development has not been thoroughly evaluated. We ascertained the presence of the SRY gene and SRY protein in the ovotestis. MATERIALS AND METHODS: We evaluated 8 ovotestes by cytogenetic analysis of fibroblast cell culture and analysis of gonadal tissue by polymerase chain reaction to detect the SRY gene and by immunohistochemistry with a monoclonal antibody to human recombinant SRY protein. RESULTS: Fibroblast culture of the ovotestes demonstrated a 46XX karyotype. By polymerase chain reaction all 8 ovotestes demonstrated the SRY gene at low levels. By immunohistochemistry SRY protein was detected in all ovotestes, predominantly in Sertoli and germ cells. CONCLUSIONS: The SRY gene has a role in ovotestis genesis. Mosaicism with a Y bearing cell line in the gonad is a possible explanation and further study is warranted
— id: 34765, year: 2002, vol: 167, page: 1828, stat: Journal Article,

An effective pooling strategy for feasible newborn screening of GBJ-2 gene mutations
Caggana, M; Duva, S; Ostrer, H; Oddoux, C; Ruben, R; Pass, K
2001 OCT ;69(4):426-426, American journal of human genetics
— id: 54823, year: 2001, vol: 69, page: 426, stat: Journal Article,

Design and development of an Ashkenazi Jewish mutation panel using MALDI-TOF mass spectrometer
Khoja, H; Nagashima, J; Giannoukos, G; Leushner, J; Oddoux, C; Ostrer, H; McGinniss, M
2001 NOV ;47(11):2082-2082, Clinical chemistry
— id: 54840, year: 2001, vol: 47, page: 2082, stat: Journal Article,

Perilymphatic fistulae associated with DFNB1-related hearing loss
Oddoux, C; Ruben, RJ; Ostrer, H
2001 OCT ;69(4):426-426, American journal of human genetics
— id: 54824, year: 2001, vol: 69, page: 426, stat: Journal Article,

Paternally transmitted recurrent true-hermaphroditism associated with SRY mosaicism
Oddoux, C; Yee, H; Clarke, V; Clayton, CM; McElreavey, K; MacGillivray, M; Ostrer, H
2000 OCT ;67(4):149-149, American journal of human genetics
— id: 54428, year: 2000, vol: 67, page: 149, stat: Journal Article,

Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population
Aksentijevich I; Torosyan Y; Samuels J; Centola M; Pras E; Chae JJ; Oddoux C; Wood G; Azzaro MP; Palumbo G; Giustolisi R; Pras M; Ostrer H; Kastner DL
1999 Apr;64(4):949-962, American journal of human genetics
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region
— id: 20350, year: 1999, vol: 64, page: 949, stat: Journal Article,

Prevalence of Bloom syndrome heterozygotes among Ashkenazi Jews
Oddoux C; Clayton CM; Nelson HR; Ostrer H
1999 Apr;64(4):1241-1243, American journal of human genetics
— id: 34768, year: 1999, vol: 64, page: 1241, stat: Journal Article,

Mendelian diseases among Roman Jews: implications for the origins of disease alleles
Oddoux C; Guillen-Navarro E; Ditivoli C; Dicave E; Cilio MR; Clayton CM; Nelson H; Sarafoglou K; McCain N; Peretz H; Seligsohn U; Luzzatto L; Nafa K; Nardi M; Karpatkin M; Aksentijevich I; Kastner D; Axelrod F; Ostrer H
1999 Dec;84(12):4405-4409, Journal of clinical endocrinology & metabolism
The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin
— id: 8259, year: 1999, vol: 84, page: 4405, stat: Journal Article,

Genetic heterogeneity in hereditary and autonomic sensory neuropathy type 4 (HSAN4)
Oddoux, C; Wang, J; Clayton, CM; Hilz, M; Cilio, R; Bertini, E; Mayaan, C; Blumenfeld, A; Axelrod, F; Ostrer, H
1999 OCT ;65(4):A482-A482, American journal of human genetics
— id: 53834, year: 1999, vol: 65, page: A482, stat: Journal Article,

TbetaR-I(6A) is a candidate tumor susceptibility allele
Pasche B; Kolachana P; Nafa K; Satagopan J; Chen YG; Lo RS; Brener D; Yang D; Kirstein L; Oddoux C; Ostrer H; Vineis P; Varesco L; Jhanwar S; Luzzatto L; Massague J; Offit K
1999 Nov 15;59(22):5678-5682, Cancer research
We have previously described a type I transforming growth factor (TGF)-beta receptor (TbetaR-I) polymorphic allele, TbetaR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TbetaR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TbetaR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TbetaR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TbetaR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TbetaR-I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TbetaR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TbetaR-I, we established stably transfected TbetaR-I and TbetaR-I(6A) cell lines. We found that, compared to TbetaR-I, TbetaR-I(6A) was impaired as a mediator of TGF-beta antiproliferative signals. We conclude that TbetaR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-beta-mediated growth inhibition
— id: 34767, year: 1999, vol: 59, page: 5678, stat: Journal Article,

Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness
Morell RJ; Kim HJ; Hood LJ; Goforth L; Friderici K; Fisher R; Van Camp G; Berlin CI; Oddoux C; Ostrer H; Keats B; Friedman TB
1998 Nov 19;339(21):1500-1505, New England journal of medicine
BACKGROUND: Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS: We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS: Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS: The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations
— id: 57210, year: 1998, vol: 339, page: 1500, stat: Journal Article,

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes
Stephens JC; Reich DE; Goldstein DB; Shin HD; Smith MW; Carrington M; Winkler C; Huttley GA; Allikmets R; Schriml L; Gerrard B; Malasky M; Ramos MD; Morlot S; Tzetis M; Oddoux C; di Giovine FS; Nasioulas G; Chandler D; Aseev M; Hanson M; Kalaydjieva L; Glavac D; Gasparini P; Kanavakis E; Claustres M; Kambouris M; Ostrer H; Duff G; Baranov V; Sibul H; Metspalu A; Goldman D; Martin N; Duffy D; Schmidtke J; Estivill X; O'Brien SJ; Dean M
1998 Jun;62(6):1507-1515, American journal of human genetics
The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations
— id: 57348, year: 1998, vol: 62, page: 1507, stat: Journal Article,

Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC
Laken SJ; Petersen GM; Gruber SB; Oddoux C; Ostrer H; Giardiello FM; Hamilton SR; Hampel H; Markowitz A; Klimstra D; Jhanwar S; Winawer S; Offit K; Luce MC; Kinzler KW; Vogelstein B
1997 Sep;17(1):79-83, Nature genetics
Approximately 130,000 cases of colorectal cancer (CRC) are diagnosed in the United States each year, and about 15% of these have a hereditary component. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC. Truncating APC mutations are responsible for FAP, and defective mismatch repair genes cause HNPCC. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition
— id: 34769, year: 1997, vol: 17, page: 79, stat: Journal Article,

Genetic evidence for a common origin among Roman Jews and Ashkenazi Jews
Oddoux, C; Guillen-Navarro, E; Clayton, CM; Nelson, H; Peretz, H; Seligsohn, U; Luzzatto, L; Nardi, M; Karpatkin, M; DiTivoli, C; DiCave, E; Axelrod, F; Ostrer, H
1997 OCT ;61(4):A207-A207, American journal of human genetics
— id: 53606, year: 1997, vol: 61, page: A207, stat: Journal Article,

X-inactivation and cytogenetic studies in a family with sensorineural hearing loss and Turner syndrome
Sculerati N; Perle MA; Oddoux C; Clayton CM; Ostrer H
1997 Dec;117(6):S221-S225, Otolaryngology, head & neck surgery
— id: 8321, year: 1997, vol: 117, page: S221, stat: Journal Article,

Severe factor XI deficiency in an Arab family associated with a novel mutation in exon 11
Wistinghausen B; Reischer A; Oddoux C; Ostrer H; Nardi M; Karpatkin M
1997 Dec;99(3):575-577, British journal of haematology
We investigated an 8-year-old Arab girl with severe factor XI deficiency; one sibling and her father also have severe factor XI deficiency. Her parents and her father's parents are first cousins. Restriction analysis and DNA sequencing excluded the type I, II, III and IV mutations. We demonstrated a previously undescribed C-->A mutation at nucleotide 1254 in exon 11 resulting in a threonine to asparagine (T-->N) substitution at amino acid 386. We postulate that this substitution interferes with folding and secretion of the molecule
— id: 12203, year: 1997, vol: 99, page: 575, stat: Journal Article,

High-level inducible expression of visual pigments in transfected cells
Kazmi MA; Dubin RA; Oddoux C; Ostrer H
1996 Aug;21(2):304-311, Biotechniques
A method for high-level expression of a functionally active, recombinant human red cone opsin was developed by adding the coding sequence for the C-terminal epitope of bovine rhodopsin onto the C terminus of the cone opsin and cloning the resulting construct into the vector pMEP4 beta. The recombinant pMEP4 beta vector was transfected stably into 293-EBNA cells, and expression of the cone opsin was induced by the addition of CdCl2 into the medium. The recombinant cone opsin was reconstituted with 11-cis retinal and purified by immunoaffinity chromatography. Spectral analysis prior to and following photobleaching confirmed its identity as a red cone opsin. The protein was targeted to the cell membrane and activated bovine transducin
— id: 12567, year: 1996, vol: 21, page: 304, stat: Journal Article,

The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%
Oddoux C; Struewing JP; Clayton CM; Neuhausen S; Brody LC; Kaback M; Haas B; Norton L; Borgen P; Jhanwar S; Goldgar D; Ostrer H; Offit K
1996 Oct;14(2):188-190, Nature genetics
Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations
— id: 8021, year: 1996, vol: 14, page: 188, stat: Journal Article,

Hearing loss in Turner syndrome
Sculerati N; Oddoux C; Clayton CM; Lim JW; Oster H
1996 Aug;106(8):992-997, Laryngoscope
A retrospective study was undertaken to answer the following questions: Is the sensorineural hearing loss (SNHL) in Turner syndrome progressive? Can the occurrence of hearing loss be explained by the parental origin of the intact X chromosome? Twenty-four individuals recruited through the Turner Syndrome Society completed a questionnaire and submitted sufficient medical records to determine their otologic status. The majority (21/24) have had problematic otitis media (OM), and two thirds (16/24) have SNHL. In seven of the Turner subjects (age range: 12 to 51 years), gradual progressive SNHL began in late childhood or early adulthood. Molecular techniques showed no correlation between parental origin of the retained X chromosome and hearing status in 17 Turner subjects and at least one of their parents. SNHL and frequent OM appear to be independent variables that are both present in Turner syndrome. It is postulated that the presence of unpaired genes on the X chromosome may account for hearing loss and other phenotypic abnormalities seen in this syndrome
— id: 12578, year: 1996, vol: 106, page: 992, stat: Journal Article,

Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population
Kronn D; Oddoux C; Phillips J; Ostrer H
1995 Nov;57(5):1250-1252, American journal of human genetics
— id: 57316, year: 1995, vol: 57, page: 1250, stat: Journal Article,

PREVALENCE OF CANAVAN-DISEASE HETEROZYGOTES IN THE NEW-YORK METROPOLITAN ASHKENAZI POPULATION
KRONN, D; ODDOUX, C; PHILLIPS, J; OSTRER, H
1995 OCT ;57(4):944-944, American journal of human genetics
— id: 86714, year: 1995, vol: 57, page: 944, stat: Journal Article,

Prenatal diagnostic testing for familial dysautonomia using linked genetic markers
Oddoux C; Reich E; Axelrod F; Blumenfeld A; Maayan C; Slaugenhaupt S; Gusella J; Ostrer H
1995 Sep;15(9):817-826, Prenatal diagnosis
Familial dysautonomia (FD), a recessively inherited disease, has been mapped to chromosome 9q31. Highly polymorphic dinucleotide repeat markers flanking the genetic locus and at the same genetic location have been identified. We describe the prenatal diagnosis of FD using linkage and linkage disequilibrium analyses with these markers. Twelve families were analysed for informativeness and of these, seven went on to have prenatal testing (a total of eight fetuses tested). All of these fetuses were predicted to be heterozygous unaffected (FD carriers). Seven fetuses have come to term and are normal. In the absence of a recombinant proband, a panel of three proximal and three distal markers is sufficient to provide informative flanking markers and an 87-96 per cent likelihood of a highly predictive test. In an additional family at 1:4 risk for FD, no DNA was available from the propositus. This family was analysed using linkage disequilibrium to the :18 allele of the tightly linked marker D9S58 in conjunction with linkage analysis using data from two unaffected children. Prenatal diagnosis in this family indicated an affected fetus
— id: 6853, year: 1995, vol: 15, page: 817, stat: Journal Article,

Renin gene promoter activity in GC cells is regulated by cAMP and thyroid hormone through Pit-1-dependent mechanisms
Gilbert MT; Sun J; Yan Y; Oddoux C; Lazarus A; Tansey WP; Lavin TN; Catanzaro DF
1994 Nov 11;269(45):28049-28054, Journal of biological chemistry
Transcriptional activity of human renin gene (hREN) 5'-flanking DNA sequences in pituitary cells is highly dependent on binding of the pituitary-specific transcription factor Pit-1. Pit-1 has been implicated in cAMP regulation of a number of pituitary genes and has also been shown to interact with thyroid hormone (T3) receptors in mediating T3 responsiveness of the rat growth hormone gene. In the present study we examine the effects of forskolin and T3 on the expression of luciferase hybrid genes containing hREN 5'-flanking DNAs (hREN.luc) transiently transfected into the pituitary cell line GC. Basal activities of all hREN.luc constructs transfected into cells grown in media containing serum stripped of hormones were low. Addition of forskolin stimulated expression up to 48-fold, depending on the hREN sequences present. The hREN sequence -148 to +18 was sufficient for both maximal expression and maximal stimulation by forskolin. Mutagenesis of the Pit-1 site between -82 and -58 reduced forskolin induction 4-5-fold. In addition to the Pit-1 site, the sequence between -148 and -98 was also required for maximal activity and forskolin induction. T3 on its own had no effect on hREN promoter activity in GC cells, but suppressed the effects of forskolin. Gel mobility shift and Western blot analyses indicated that forskolin treatment had no effect on Pit-1 DNA binding or Pit-1 levels. However, T3 reduced Pit-1 levels which was reflected in lower DNA binding under the conditions employed. Taken together, these findings emphasize the importance of cAMP-dependent mechanisms in directing renin gene expression
— id: 34770, year: 1994, vol: 269, page: 28049, stat: Journal Article,

Characterization of a chicken hepatoma cell line with a specific defect in fibrinogen secretion
Oddoux C; Grieninger G
1994 Mar;19(3):682-687, Hepatology
This study characterizes plasma protein synthesis and its hormonal regulation in a chicken hepatoma cell line, with particular emphasis on fibrinogen. Whereas virtually all aspects of hemopexin, transferrin and albumin production in these cells corresponded to those of cultured primary hepatocytes, fibrinogen was not secreted. Analysis of fibrinogen subunit synthesis revealed a specific defect in synthesis of one subunit, gamma, correlating with a lack of its mRNA. Pulse-chase and electron microscopic studies demonstrate that, despite the inability of these cells to secrete the A alpha and B beta subunits produced, there is no long-term accumulation of unsecreted fibrinogen. The B beta fibrinogen subunits are largely degraded 2 hr after synthesis. During this time, approximately half of the A alpha subunits are degraded; the rest are converted to the glycosylated form. The implications of this type of defect with respect to the pathogenesis of fibrinogen storage disease are discussed
— id: 34773, year: 1994, vol: 19, page: 682, stat: Journal Article,

Fibrinogen assembly: insights from chicken hepatocytes
Oddoux C; Grieninger G
1994 Mar;19(3):688-693, Hepatology
In all vertebrate species studied, the complex, disulfide-linked structure of fibrinogen is essentially the same: a hexamer assembled from three different subunits (A alpha, B beta, gamma)2. This study utilized species differences in fibrinogen subunit monomer pools to address the question of how these surplus subunit pools may affect the assembly process. We used a chicken model system in which B beta and gamma-subunits are present in excess, in contrast to the A alpha and gamma-subunit surplus found in human model systems. Analysis was based on pulse-chase experiments with electrophoretic separation of intracellular forms and secreted fibrinogen on reducing and nonreducing gels. The chicken liver-derived cells employed for this purpose, primary hepatocytes and a hepatoma cell line with a fortuitous defect in fibrinogen synthesis, together offer advantages over human systems for resolving the complexes formed in the early stages of assembly. The results demonstrate that in chicken hepatocytes there is an initial binding of gamma to A alpha subunits rather than to B beta subunits, as occurs in human hepatoma cells. Nevertheless, the presence of similar intracellular fibrinogen-related forms in both chicken- and human-derived cells, in the context of their differing subunit monomer pools, suggests an assembly pathway common to both species, with the versatility to be regulated by limitation of A alpha or B beta subunit production
— id: 34772, year: 1994, vol: 19, page: 688, stat: Journal Article,

Pituitary-specific transcription factor (Pit-1) binding site in the human renin gene 5'-flanking DNA stimulates promoter activity in placental cell primary cultures and pituitary lactosomatotropic cell lines
Sun J; Oddoux C; Gilbert MT; Yan Y; Lazarus A; Campbell WG Jr; Catanzaro DF
1994 Oct;75(4):624-629, Circulation research
Renin gene expression is limited to a number of specific tissues, including the kidney, adrenal glands, reproductive organs (of particular relevance to this study, the placenta), and the pituitary gland. In the present study, we investigated the human renin (hRen) 5'-flanking DNA sequences required to drive the expression of a luciferase reporter gene in placental and pituitary cells and in two cell lines, 293 and JEG-3, which have been proposed as model systems with which to study transcriptional regulation of renin genes. The activities of specific sequences in the hRen 5'-flanking DNA sequences in human placental cell primary cultures were very similar to those that we previously reported in pituitary cells, suggesting the involvement of common promoter elements and related transcription factors. Accordingly, the binding site for the pituitary-specific transcription factor (Pit-1) was the major determinant of renin promoter activity in both pituitary and placental cells. Gel mobility shift analysis showed a placental nuclear factor with a gel mobility different from that of Pit-1. However, Northern blot analysis failed to demonstrate abundant Pit-1-related mRNAs in renin-expressing cultures of chorionic and decidual cells, suggesting that the placental factor is not closely related to Pit-1. Although a factor from 293 cells also bound to the Pit-1 site, it had gel mobility shift characteristics different from Pit-1 and the placental factor. Moreover, the low promoter activity in 293 cells was independent of this site or, indeed, of sequences upstream from the TATA box. In JEG-3 cells, renin 5'-flanking DNA sequences showed virtually no transcriptional activity.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 34771, year: 1994, vol: 75, page: 624, stat: Journal Article,

Characterization of the chicken apolipoprotein A-I gene 5'-flanking region
Bhattacharyya N; Chattapadhyay R; Oddoux C; Banerjee D
1993 Sep;12(7):597-604, DNA & cell biology
Apolipoprotein A-I (apoA-I) is a major protein component of plasma high-density lipoprotein in all species studied, and plays an important role in cholesterol homeostasis. In an earlier study, we cloned and structurally characterized the chicken apoA-I gene. In this study, the 5'-flanking region of the chicken apoA-I gene was sequenced and functionally characterized. Sequence analysis of the 510-nucleotide 5' upstream region revealed the presence of TATA and CCAAT boxes. In addition, we identified binding sites for several transcription factors such as Sp1, AP1, and NFI.2. When the 5' fragment was ligated into a promoterless CAT vector and transfected into a chicken hepatocarcinoma cell line (LMH), the bacterial chloramphenicol acetyl transferase (CAT) gene was expressed, suggesting transcriptional regulation is associated with this region. Transfection studies with other 5' deletion constructs revealed that the sequence spanning the region -82 to +87 contained the major transcriptional activity. DNase I footprinting, gel retardation, and Southwestern blot analyses showed that the fragment interacts with nuclear proteins
— id: 34774, year: 1993, vol: 12, page: 597, stat: Journal Article,

Promoter activity of human renin 5'-flanking DNA sequences is activated by the pituitary-specific transcription factor Pit-1
Sun J; Oddoux C; Lazarus A; Gilbert MT; Catanzaro DF
1993 Jan 25;268(3):1505-1508, Journal of biological chemistry
Although the renal juxtaglomerular cell is the source of circulating renin, the renin gene is also expressed at a number of extrarenal sites including lactotrope cells of human and ovine pituitaries. In the present study, we demonstrate that GC cells, a pituitary lactotrope precursor cell line, efficiently express transiently transfected hybrid genes containing human renin 5'-flanking DNA sequences -148/+11. Gel mobility shift competition analyses show that a highly conserved sequence in human and rodent renin 5'-flanking DNAs (human coordinates: -80/-58) binds a nuclear factor from GC cells, most likely the pituitary-specific factor Pit-1. Deletional and mutational analyses demonstrate that this site is a major determinant of renin promoter activity in GC cells. Transfection of a Pit-1 expression construct into HeLa cells, where activity of the human renin promoter is low, stimulates expression of cotransfected renin-luciferase constructs. Moreover, activation of the human renin promoter by co-expression of Pit-1 is dependent on an intact Pit-1 site. Taken together, these data strongly suggest that Pit-1 activates pituitary renin gene expression. This finding raises the possibility that member(s) of the POU family of transcription factors, of which Pit-1 is an archetypal member, may direct renin expression in other tissues, including the kidney
— id: 34775, year: 1993, vol: 268, page: 1505, stat: Journal Article,

Carboxy-terminal-extended variant of the human fibrinogen alpha subunit: a novel exon conferring marked homology to beta and gamma subunits
Fu Y; Weissbach L; Plant PW; Oddoux C; Cao Y; Liang TJ; Roy SN; Redman CM; Grieninger G
1992 Dec 8;31(48):11968-11972, Biochemistry
Similarities between the N-terminal regions of the three subunits of the clotting protein fibrinogen--(alpha beta gamma)2--suggest that they evolved from a common progenitor. However, to date no human alpha chain has been found with the strong C-terminal homology shared by the beta and gamma chains. Here we examine the natural product of a novel fibrinogen alpha chain transcript bearing a separate open reading frame that supplies the missing C-terminal homology to the other chains. Additional splicing leads to the use of this extra sequence as a sixth exon elongating the alpha chain by 35%. Since the extended alpha chain (alpha E) is assembled into fibrinogen molecules and its synthesis is enhanced by interleukin-6, it suggests participation in both the acute phase response and normal physiology
— id: 34776, year: 1992, vol: 31, page: 11968, stat: Journal Article,

Assembly and secretion of fibrinogen. Degradation of individual chains
Roy S; Yu S; Banerjee D; Overton O; Mukhopadhyay G; Oddoux C; Grieninger G; Redman C
1992 Nov 15;267(32):23151-23158, Journal of biological chemistry
Hep G2 cells produce surplus A alpha and gamma fibrinogen chains. These excess chains, which are not secreted, exist primarily as free gamma chains and as an A alpha-gamma complex. We have determined the intracellular location and the degradative fate of these polypeptides by treatment with endoglycosidase-H and by inhibiting lysosomal enzyme activity, using NH4Cl, chloroquine, and leupeptin. Free gamma chain and the gamma component of A alpha-gamma are both cleaved by endoglycosidase-H, indicating that the gamma chains accumulate in a pre-Golgi compartment. Lysosomal enzyme inhibitors did not affect the disappearance of free gamma chains but inhibited A alpha-gamma by 50%, suggesting that A alpha-gamma is degraded in lysosomes. The degradative fate of individual chains was determined in transfected COS cells which express but do not secrete single chains. Leupeptin did not affect B beta chain degradation, had very little affect on gamma chain, but markedly inhibited A alpha chain degradation. Antibody to immunoglobulin heavy chain-binding protein (GRP 78) co-immunoprecipitated B beta but not A alpha or gamma chains. Preferential binding of heavy chain-binding protein to B beta was also noted in Hep G2 cells and in chicken hepatocytes. Taken together these studies indicate that B beta and gamma chains are degraded in the endoplasmic reticulum, but only B beta is bound to BiP. By contrast A alpha chains and the A alpha-gamma complex undergo lysosomal degradation
— id: 34777, year: 1992, vol: 267, page: 23151, stat: Journal Article,

The beta chain of chicken fibrinogen contains an atypical thrombin cleavage site
Weissbach L; Oddoux C; Procyk R; Grieninger G
1991 Apr 2;30(13):3290-3294, Biochemistry
A cDNA corresponding to almost the entire coding region of the mRNA for the beta chain of chicken fibrinogen was sequenced. At the protein level, significant homology to the beta subunits of other vertebrate fibrinogens was found, with the highest degree of amino acid identity localized in the C-terminal region. In general, features conserved in the fibrinogens from other species also characterize the chicken sequence, including the cysteine motifs bordering an alpha-helical permissive region of fixed length and a single glycosylation site in the C-terminal region. However, the site of thrombin-catalyzed cleavage, which in other species consists of an Arg-Gly peptide bond, is instead an Arg-Ala bond in the chicken beta chain. The Ala was confirmed directly from a sequencing analysis of the purified beta chain of chicken fibrin. This finding may explain the observed slow clotting time of chicken fibrinogen relative to that of other species
— id: 34778, year: 1991, vol: 30, page: 3290, stat: Journal Article,

Regulation of fibrinogen synthesis and secretion by the chicken hepatocyte
Grieninger G; Oddoux C; Diamond L; Weissbach L; Plant PW
1989 ;557(13):257-70, discussion 270, Annals of the New York Academy of Sciences
— id: 34779, year: 1989, vol: 557, page: 257, stat: Journal Article,