Hereditary Deafness

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Hereditary Deafness

• Laura Kissock
• 5 December 2006

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Hereditary Deafness

• Prelingual non-syndromic (isolated) deafness is
  the most frequent hereditary sensory defect. In
  gt80 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

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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.

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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.

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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

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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
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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.
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Visualization of proteins structure/ function
relationship
Unaltered Connexin 43
Connexin 43 with mutation

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(No Transcript)
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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
  May69(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
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