Research Outline

Research in our laboratory is focused upon two distinct proteins connexin 26 (CX26) and the nonmuscle myosin (MYH9) and their biological role in hearing and its dysfunction. CX26 is a transmembrane protein that forms a channel enabling passage of small molecules between cells while MYH9 is an intracellular motor protein considered to have diverse functions including a role in cytokinesis and cell shape. Mutations in the genes encoding CX26 or MYH9 is causally linked to non-syndromic and syndromic forms of hereditary hearing loss (HHL), thus underscoring their critical role in auditory function. Mutations of Cx26 are account for nearly 50% of congenital deafness in humans. Prevalence of MYH9 mutations and their contribution to hearing loss remains to be determined. The general strategy that is used to decipher the role of these two proteins in auditory function is through development and characterization of in vitro and in vivo models with CX26 or MYh9 dysfunction.

Faculty

Anand N Mhatre, PhD - Director

Lab Personnel

Yan Li, PhD - Post-doctoral Fellow
Jian Luca Armas, MD - Post-doctoral Fellow
Kevin Wang, BSc - Medical Student
Abdel Maghnouj, MSc - Research Associate
Graham Atkins, BA - Research Associate

Education

The laboratory of Molecular Otology and Molecular Genetics welcomes Medical Students and Residents interested in pursuing short term or long term projects in auditory research.

Publications

Mhatre, AN, Trifiro, MA, Kaufman, M, Kazemi-Esfarjani, P, Figlewicz, D, Rouleau, G and Pinsky, L (1993). "Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy [published erratum appears in Nat Genet 1994 Feb;6(2):214]." Nat Genet 5(2): 184-8.

Lalwani, AK, Walsh, BJ, Reilly, PG, Muzyczka, N and Mhatre, AN (1996). "Development of in vivo gene therapy for hearing disorders: introduction of adeno-associated virus into the cochlea of the guinea pig." Gene Ther 3(7): 588-92.

Lalwani, AK, Han, JJ, Walsh, BJ, Zolotukhin, S, Muzyczka, N and Mhatre, AN (1997). "Green fluorescent protein as a reporter for gene transfer studies in the cochlea." Hear Res 114(1-2): 139-47.

Lalwani, A, Walsh, B, Reilly, P, Carvalho, G, Zolotukhin, S, Muzyczka, N and Mhatre, AN (1998). "Long-term in vivo cochlear transgene expression mediated by recombinant adeno-associated virus." Gene Ther 5(2): 277-81.

Lalwani, AK, Walsh, BJ, Carvalho, GJ, Muzyczka, N and Mhatre, AN (1998). "Expression of adeno-associated virus integrated transgene within the mammalian vestibular organs." Am J Otol 19(3): 390-5.

Mhatre, AN, Charachon, G, Alper, SL and Lalwani, AK (1998). "The guinea pig cochlear AE2 anion exchanger: cDNA cloning and in situ localization within the cochlea." Biochim Biophys Acta 1414(1-2): 1-15.

Han, JJ, Mhatre, AN, Wareing, M, Pettis, R, Gao, WQ, Zufferey, RN, Trono, D and Lalwani, AK (1999). "Transgene expression in the guinea pig cochlea mediated by a lentivirus-derived gene transfer vector." Hum Gene Ther 10(11): 1867-73.

Lalwani, AK, Luxford, WM, Mhatre, AN, Attaie, A, Wilcox, ER and Castelein, CM (1999). "A new locus for nonsyndromic hereditary hearing impairment, DFNA17, maps to chromosome 22 and represents a gene for cochleosaccular degeneration [letter]." Am J Hum Genet 64(1): 318-23.

Mhatre, AN, Steinbach, S, Hribar, K, Hoque, AT and Lalwani, AK (1999). "Identification of aquaporin 5 (AQP5) within the cochlea: cDNA cloning and in situ localization." Biochem Biophys Res Commun 264(1): 157-62.

Wareing, M, Mhatre, AN, Pettis, R, Han, JJ, Haut, T, Pfister, MH, Hong, K, Zheng, WW and Lalwani, AK (1999). "Cationic liposome mediated transgene expression in the guinea pig cochlea." Hear Res 128(1-2): 61-9.

Lalwani, AK, Goldstein, JA, Kelley, MJ, Luxford, W, Castelein, CM and Mhatre, AN (2000). "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9." Am J Hum Genet 67(5): 1121-8. Lalwani, AK and Mhatre, AN (2000). "Cochlear gene therapy." Adv Otorhinolaryngol 56: 275-8.

Jero, J, Mhatre, AN, Tseng, CJ, Stern, RE, Coling, DE, Goldstein, JA, Hong, K, Zheng, WW, Hoque, AT and Lalwani, AK (2001). "Cochlear gene delivery through an intact round window membrane in mouse." Hum Gene Ther 12(5): 539-48.

Mhatre AN, Jero J, Chiappini I, Bolasco G, Barbara M, Lalwani AK. Aquaporin-2 Expression in the Mammalian Cochlea and Investigation of its Role in Meniere's Disease. Hear Res. 2002, 170(1-2):59-69.

Lalwani AK, Han JJ, Castelein CM, Carvalho GJ, Mhatre AN. In Vitro and In Vivo Assessment of AAV-BDNF's Ability to Enhance Spiral Ganglion Cell Survival Following Ototoxic Insult. Laryngoscope, 112(8 Pt 1):1325-34.

Mhatre AN, Kim Y, Lalwani AK. Macrothrombocytopenia and Progressive Deafness is due to MYH9 Mutation. Otology and Neurotology, Otol Neurotol. 2003 Mar;24(2):205-9.

Mhatre AN, Stern R, Lei J, Lalwani AK. Aquaporin 4 (Aqp4) Expression in the Mammalian Inner ear and Cloning of the Rat Aqp4 5'UTR. Biochem Biophys Res Commun. 2002 Oct 4;297(4):987-96.

Mhatre AN, Weld E, Lalwani AK. Mutation Analysis of Connexin 31 (GJB3) in Sporadic Nonsyndromic Hearing Impairment. Clin Genet. 2003 Feb;63(2):154-9.

Mhatre AN, Li J, Chen AF, Yost CS, Smith RJH, Kindler CH, and Lalwani AK. Genomic Structure, Cochlear Expression and Mutation Screening of KCNK6, a Candidate Gene for DFNA4. J Neurosci Res. 2004, 75(1):25-31.

Mhatre AN, Li J, Kim Y, Coling DE, Lalwani AK. Cloning and developmental expression of nonmuscle myosin IIA (Myh9) in the mammalian inner ear. J Neurosci Res. 2004, 76(3):296-305

Mhatre AN, Li Y, Feng L and,Lalwani AK. SDHB, SDHC and SDHD Mutations in Sporadic and Familial Head and Neck Paragangliomas, Clinical Genetics, 2004, In Press.