Hereditary Deafness Laura Kissock 5 December 2006 Hereditary

Hereditary Deafness Laura Kissock 5 December 2006

Hereditary Deafness § Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. § One gene responsible encodes connexin 26 § Mutations in Cx 26 represent a major cause of recessively inherited prelingual deafness

Connexin 26 § Connexins (Cx) form gap junctions that allow the exchange of small metabolites and ions. § In the inner ear, Cx 26 is the major gap junction protein § Mutations in the Cx 26 -encoding gene, GJB 2, are the most frequent cause of autosomal recessive non-syndromic hearing loss. § Reduced potassium recirculation in the inner ear and abnormalities in the exchange of other metabolites through the cochlear gap.

GJB 2 Mutations § A mutation consisting of deletion of 1 guanine (G) in a run of 6 guanines extending from position 30 to position 35 in the GJB 2 gene has been observed § Causes a frameshift of the coding sequence leading to premature chain termination at the twelfth amino acid. § Arise due to the run of Gs being a mutation hotspot.

Homo sapiens connexin 26 (GJB 2) gene, complete cds 1 atggattggg gcacgctgca gacgatcctg gggggtgtga acaaacactc caccagcatt 61 ggaaagatct ggctcaccgt cctcttcatt tttcgcatta tgatcctcgt tgtggctgca 121 aaggaggtgt ggggagatga gcaggccgac tttgtctgca acaccctgca gccaggctgc 181 aagaacgtgt gctacgatca ctacttcccc atctcccaca tccggctatg ggccctgcag 241 ctgatcttcg tgtccacgcc agcgctccta gtggccatgc acgtggccta ccggagacat 301 gagaagaaga ggaagttcat caagggggag ataaatagtg aatttaagga catcgaggag 361 atcaaaaccc agaaggtccg catcgaaggc tccctgtggt ggacctacac aagcagcatc 421 ttcttccggg tcatcttcga agccgccttc atgtacgtct tctatgtcat gtacgacggc 481 ttctccatgc agcggctggt gaagtgcaac gcctggcctt gtcccaacac tgtggactgc 541 tttgtgtccc ggcccacgga gaagactgtc ttcacagtgt tcatgattgc agtgtctgga 601 atttgcatcc tgctgaatgt cactgaattg tgttatttgc taattagata ttgttctggg 661 aagtcaaaaa agccagttta a

35 del. G mutation in GJB 2 1 atggattggg gcacgctgca gacgatcctg gggggtgtga acaaacactc caccagcatt 61 ggaaagatct ggctcaccgt cctcttcatt tttcgcatta tgatcctcgt tgtggctgca 121 aaggaggtgt ggggagatga gcaggccgac tttgtctgca acaccctgca gccaggctgc 181 aagaacgtgt gctacgatca ctacttcccc atctcccaca tccggctatg ggccctgcag 241 ctgatcttcg tgtccacgcc agcgctccta gtggccatgc acgtggccta ccggagacat 301 gagaagaaga ggaagttcat caagggggag ataaatagtg aatttaagga catcgaggag 361 atcaaaaccc agaaggtccg catcgaaggc tccctgtggt ggacctacac aagcagcatc 421 ttcttccggg tcatcttcga agccgccttc atgtacgtct tctatgtcat gtacgacggc 481 ttctccatgc agcggctggt gaagtgcaac gcctggcctt gtcccaacac tgtggactgc 541 tttgtgtccc ggcccacgga gaagactgtc ttcacagtgt tcatgattgc agtgtctgga 601 atttgcatcc tgctgaatgt cactgaattg tgttatttgc taattagata ttgttctggg 661 aagtcaaaaa agccagttta a

Amino acid sequence of GJB 2 1 mdwgtlqtil ggvnkhstsi gkiwltvlfi frimilvvaa kevwgdeqad fvcntlqpgc 61 knvcydhyfp ishirlwalq lifvstpall vamhvayrrh ekkrkfikge iksefkdiee 121 iktqkvrieg slwwtytssi ffrvifeaaf myvfyvmydg fsmqrlvkcn awpcpntvdc 181 fvsrptektv ftvfmiavsg icillnvtel cyllirycsg kskkpv Amino acids in 35 del. G mutation in GJB 2 1 mdwgtlqtil gv Deletion changes codons from ggt gtg to gtg tga which correlates in an amino acid change of glysine, valine to valine, stop.

Visualization of protein’s structure/ function relationship Unaltered Connexin 43 with mutation

References § del Castillo, I. ; Villamar, M. ; Moreno-Pelayo, M. A. ; del Castillo, F. J. ; Alvarez, A. ; Telleria, D. ; Menendez, I. ; Moreno, F. : “A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. ” New Eng. J. Med. 346: 243 -249, 2002. Pub. Med ID : 11807148 § Willems, P. J. : “Genetic causes of hearing loss. ” New Eng. J. Med. 342: 1101 -1109, 2000. Pub. Med ID : 10760311 § Petersen MB, Willems PJ. “Non-syndromic, autosomal-recessive deafness. ”Clin Genet. 2006 May; 69(5): 371 -92. Review. PMID: 16650073 § Carrasquillo, M. M. ; Zlotogora, J. ; Barges, S. ; Chakravarti, A. : “Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. ” Hum. Molec. Genet. 6: 2163 -2172, 1997. Pub. Med ID : 9328482 § Mese, G. ; Londin, E. ; Mui, R. ; Brink, P. R. ; White, T. W. : “Altered gating properties of functional Cx 26 mutants associated with recessive non -syndromic hearing loss. ” Hum. Genet. 115: 191 -199, 2004. Pub. Med ID : 15241677