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Hereditary Deafness

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

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Hereditary Deafness

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  1. Hereditary Deafness Laura Kissock 5 December 2006

  2. 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 Cx26 represent a major cause of recessively inherited prelingual deafness

  3. Connexin 26 • Connexins (Cx) form gap junctions that allow the exchange of small metabolites and ions. • In the inner ear, Cx26 is the major gap junction protein • Mutations in the Cx26-encoding gene, GJB2, 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.

  4. GJB2 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 GJB2 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.

  5. 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 Homo sapiens connexin 26 (GJB2) gene, complete cds

  6. 35delG mutation in GJB2 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

  7. Amino acid sequence of GJB2 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 35delG mutation in GJB2 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.

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

  9. 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. PubMed ID : 11807148 • Willems, P. J. : “Genetic causes of hearing loss.” New Eng. J. Med. 342: 1101-1109, 2000. PubMed 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. PubMed ID : 9328482 • Mese, G.; Londin, E.; Mui, R.; Brink, P. R.; White, T. W. : “Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss.” Hum. Genet. 115: 191-199, 2004. PubMed ID : 15241677

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