Download 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
 Mutations in Cx26 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, 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.
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.
Homo sapiens connexin 26
(GJB2) 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
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
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.
Visualization of protein’s
structure/ function relationship
Unaltered Connexin 43
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.
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
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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