CDH23 SNPs

CDH23 SNPs

CDH23 (cadherin 23) on 10q22.1 is one of the better understood genes of the Usher disease complex. These genes generally encode structural proteins utilized in both hearing and visual systems -- and so at the mutational level by effects on both. Stop codons within CDH23 cause both deafness and blindness (USH1D) whereas missense alleles can affect hearing only (DFNB12). Both conditions are autosomal recessive. However one bad copy of CDH23 in conjunction with one bad allele of PCDH15 (protocadherin 15) on 10q21.1 (17 million bp over, not tandem) can give rise to the digenic disease USH1H. That has a simple physical explanation in defective heteroligomeric binding of the two terminal domains where the respective cSNPs occur.

Many Usher genes function both transiently during development of cochlea and retina and permenantly in adult structures. These functions may localize to multiple sites within each organ, for example ribbon synapses and stereocilia. CDH23 like many of these proteins has different binding partners to its cytoplasimic and extracellular domains as well as a transmembrane region. Other unrelated cell types elsewhere in the body may use these gene products though mutant alleles to date first manifest in hearing and vision. The role of CDH23 in hair tip links has recently been disentangled from its transient but critical role in hair cell development.

However some coding variants of CDH23 are simply near-normal (or even adaptive) polymorphic variants not giving rise to problems during the carrier's lifespan, though subtle subclinical effects on age related (or noise-induced) hearing loss or night vision acuity might still occur. In the past, such variations would be occasionally be detected within geneologies of affected indiviuals but not track with their disease; today, coding SNPs are far more likely to emerge -- and in far greater numbers -- simply in the course of genomic screening. That trend will only accerate with the advent of rapid screening platforms such as Nimblegen that can affordably screen the entire human proteome.

Note these myriad new cSNPs needing interpretation will come with accurate population frequencies further stratified by ethnic group distribution. That can be viewed as 'close-up' comparative genomics that complements the longer view of reduced alphabet afforded currently by CDH23 orthologs in 50-odd vertebrate genome phylogenetic tree. These considerations, along with accurate 3D models of both the cadherin module affected and protein binding partner, greatly help in interpreting disease implications of particular observed SNPs (for example E737V), yet uncertainty will remain in many instances.

Here a newly observed cSNP in a Kalahari Bushmen, heterozygous L1122V in exon 26, lies fall just before the boundary of the 11th of 27 cadherin ectodomains of the 3354 residue, 67 exon protein. This would appear unremarkable except for the observation that valine is ancestral mammalian value here which is conserved over vast phylogenetic time.

Comparative anatomy

It is recognized today that

Comparative genomics

Orthologs of CDH32 are available from 42 vertebrates in the exon containing L1122V. The following exon is quite short so difficult to obtain broadly; transcripts are uncommon so deep in a gene. This does not affect modeling because residue 1122 lies in an interdomain region anyway.

Observe that while leucine is sometimes found at this position in other species, that occurence is concentrated strictly in early diverging vertebrates. In all 33 species of tetrapods (where sound is conducted primarily through air), the value here is exclusively valine. Note in particular the four other species of great apes have valine with no indication of heterozygosity.

From this perspective, L1122V may reflect retention of the ancestral value in one allele, rather than result from de novo back mutation from a L1122L homozygote. In other words, L1122 could be viewed as a mutation apparently fixed for better or worse in all other human populatons -- at a position conserved over billions of years of branch length in phylogenetically related species.

              <----------cad10----------><------interdomain------><---cad11--->
              ................................................^.
CDH23_homSap  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQ
CDH23_panTro  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_gorGor  dNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_ponAbe  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASIPEDIPEGHSIVQ
CDH23_nomLeu  DNGPVGKRHTGTATVFITVLDVNDNRPIFLQSSYEASIPEDIPEGHSIVQ
CDH23_rheMac  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_calJac  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_tarSyr  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_micMur  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_musMus  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_ratNor  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_cavPor  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_speTri  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_oryCun  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_ochPri  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIVEGHSIVQ
CDH23_bosTau  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVSEDIPEGHSIVQ
CDH23_canFam  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_felCat  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_pteVam  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_turTru  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_susScr  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_equCab  DNGPVGKRRTGTATVFITVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_eriEur  dNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_loxAfr  DNGPVGKRRTGTTTVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_proCap  DNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASIPEDIPEGHSIVQ
CDH23_echTel  dNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSIVQ
CDH23_choHof  dNGPVGKRRTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGRSIVQ
CDH23_monDom  DNGPVGKRRTGTATIYVTVLDVNDNRPIFLQSSYEASVPEDIPEGSSIVQ
CDH23_macEug  DNGPVGKRRTGTATVYVTVLDVNDNRPIFLHSSYEASISEDIPEGSSIVQ
CDH23_ornAna  DNGPSGKRRTGTATVYVTVLDVNDNRPIFLQSSYEASVPEDIPEASSIVQ
CDH23_galGal  DNGPTGNRRTGTATVYVTVLDVNDNRPIFLQSSYEASVPEDIPAASSIVQ
CDH23_taeGut  DNGPSGNRRTGTATVYVTVLDVNDNRPIFLQSSYEVSVPEDIPAASSIVQ
CDH23_anoCar  DNGPTGKRRTGTATVHVTVLDVNDNRPYFLQSSYEATVPEDIPDYSSIVQ
CDH23_xenTro  DNGPAGNRKTGTATVSVTVLDINDNKPIFLKSSYEASVPENVPFSSSIVQ
CDH23_oryLat  DNGPAGSRRTGTATVFVEVLDVNDNRPIFLQNSYETSVLETVPQGTSILQ
CDH23_takRub  DNGPAGSRRTGTATVFVEVQDVNDNRPIFLQNSYETGILESVPQGTSILQ
CDH23_danRer  DNGPAGGRRTGTATVYVEVLDVNDNRPIFLQNSYETSVLENIPRGTSILQ
CDH23_gasAcu  DNGPAGSRRTGTATVFVEVQDVNDNRPIFLQNSYETSILESVPQRTSILK
CDH23_tetNig  DNGPAGSRRTGTATVFVEVQDVNDNRPIFLQNSYETSVLESVPQGTSILQ
CDH23_ictPun  DNGPAGDRKTGTATVYVEVLDVNDNRPIFLQNSYETTVLENVPRGSSVLQ
CDH23_calMil  DNGPAGSRRTGTATVYIRVLDVNDNRPIFLQNTYEASVPENITMSTSILQ
CDH23_petMar  DHGPAGSRRTGTTTLDVLVLDVNDNRPLFLEGSYZVSVPDNVTRGAIFLQ
              ................................................^.
CDH23_homSap  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQ
CDH23_panTro  ................................................V.
CDH23_gorGor  ................................................V.
CDH23_rheMac  ................................................V.
CDH23_calJac  ................................................V.
CDH23_pteVam  ................................................V.
CDH23_ponAbe  .....................................I..........V.
CDH23_nomLeu  ................I....................I..........V.
CDH23_tarSyr  ........R.......................................V.
CDH23_micMur  ........R.......................................V.
CDH23_musMus  ........R.......................................V.
CDH23_ratNor  ........R.......................................V.
CDH23_cavPor  ........R.......................................V.
CDH23_speTri  ........R.......................................V.
CDH23_oryCun  ........R.......................................V.
CDH23_canFam  ........R.......................................V.
CDH23_felCat  ........R.......................................V.
CDH23_turTru  ........R.......................................V.
CDH23_susScr  ........R.......................................V.
CDH23_echTel  ........R.......................................V.
CDH23_eriEur  ........R.......................................V.
CDH23_proCap  ........R............................I..........V.
CDH23_equCab  ........R.......I...............................V.
CDH23_loxAfr  ........R...T...................................V.
CDH23_choHof  ........R....................................R..V.
CDH23_bosTau  ........R.............................S.........V.
CDH23_ochPri  ..........................................V.....V.
CDH23_monDom  ........R.....IY.............................S..V.
CDH23_macEug  ........R......Y..............H......IS......S..V.
CDH23_ornAna  ....S...R......Y............................AS..V.
CDH23_galGal  ....T.N.R......Y...........................AAS..V.
CDH23_taeGut  ....S.N.R......Y...................V.......AAS..V.
CDH23_anoCar  ....T...R......H...........Y........T......DYS..V.
CDH23_xenTro  ....A.N.K......S.....I...K....K.........NV.FSS..V.
CDH23_oryLat  ....A.S.R........E.............N...T..L.TV.Q.T....
CDH23_takRub  ....A.S.R........E.Q...........N...TGIL.SV.Q.T....
CDH23_tetNig  ....A.S.R........E.Q...........N...T..L.SV.Q.T....
CDH23_gasAcu  ....A.S.R........E.Q...........N...T.IL.SV.QRT...K
CDH23_danRer  ....A.G.R......Y.E.............N...T..L.N..R.T....
CDH23_ictPun  ....A.D.K......Y.E.............N...TT.L.NV.R.S.V..
CDH23_calMil  ....A.S.R......YIR.............NT.......N.TMST....
CDH23_petMar  .H..A.S.R...T.LD.L.........L..EG..ZV...DNVTR.AIF..
   Consensus  .n..a...r...a.v..t.l.......i..qs..#as!p#.!p.g.siv.
              ................................................^.

Pseudogene issues

(to be continued shortly)