CDH23 SNPs: Difference between revisions

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[[Image:CDHe737v.jpg|left]]
[[Image:CDHe737v.jpg|left]]


Since CDH23 is known to form a homodimer in tip links -- and such binding patches can involve hydrophobic residues that otherwise would be buried -- the quaternary structure here is the main unknown. Crystallographic adjacency in the unit cell does not always reflect oligomeric solution structure. Consequently, it may not be possible to fully evaluate L1122V despite the favorable match at PDB.  
Since CDH23 is known to form a [http://www.ncbi.nlm.nih.gov/pubmed/17805295 helical homodimer] in tip links -- and such binding patches can involve hydrophobic residues that otherwise would be buried -- the quaternary structure here is the main unknown. Crystallographic adjacency in the unit cell does not always reflect oligomeric solution structure. Consequently, it may not be possible to fully evaluate L1122V despite the favorable match at PDB.  


There is no reason to think L1122V would directly affect the calcium binding motifs (LDRE, D.ND, D.D) of either adjacent cadherin domains in the manner of the [http://www.pnas.org/content/106/13/5252/F2.expansion.html E737V] salsa mouse mutation in exon 22 or D124G, R1060W, E1595K and D2202N, none of which have syndromic effects on the retina but demonstrably weaken calcium dependent binding to PCDH15 even though they do not lie in the amino-terminal [http://www.ncbi.nlm.nih.gov/pubmed/17805295?dopt=Abstract cadherin binding domains].  
There is no reason to think L1122V would directly affect the calcium binding motifs (LDRE, D.ND, D.D) of either adjacent cadherin domains in the manner of the [http://www.pnas.org/content/106/13/5252/F2.expansion.html E737V] salsa mouse mutation in exon 22 or D124G, R1060W, E1595K and D2202N, none of which have syndromic effects on the retina but demonstrably weaken calcium dependent binding to PCDH15 even though they do not lie in the amino-terminal [http://www.ncbi.nlm.nih.gov/pubmed/17805295?dopt=Abstract cadherin binding domains].  
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[[Image:USHprots.jpg]]
[[Image:USHprots.jpg]]
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=== Comparison of CDH15 domains to PCDH15 ===
=== Comparison of CDH15 domains to PCDH15 ===


Revision as of 14:18, 19 August 2009

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 partner issues in cytoplasmic (USH1C harmonin, MYO7A myosin, USH1G sans) versus extracellular and transmembrane domains. Other unrelated cell types elsewhere in the body may use these gene products though mutant alleles manifest most sensitively 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 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--->
              ....................Ca+2........................^. ....Ca2
CDH23_homSap  DNGPVGKRHTGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQ LKATDADEG
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.
              ................................................^.

Comparative anatomy

The remarkable auditory hair cell linker provided by CDH23 and PCDH15 is not a vertebrate innovation. Instead it must date back to the pre-bilateran ancestor because contemporary cnidarians such as Nematostella have a very similar overall structure that incorporates an apparent ortholog to CDH23. This cannot be plausibly attributed to convergent evolution given the extent of structural agreement. Note in mouse that the link is polarized with PCDH15 attached to the shorter hair cel and CDH23 to the longer.

CDH25compAnat.jpg

The Nematostella protein most resembling CDH23 has 6,074 residues, three transmembrane helices and 44 contiguous cadherin ectodomains with 4x-periodicity. Thus the correspondence at the protein level is imperfect. However antibodies show it is distributed on stereocilia of anemone hair bundles and required for tenticle sensitivity to vibration (prey detection). It provides both lateral and tip linkages.

Nematostella also has long but weak matches to PCDH15, namely XM_001638202 and EU289217. However upon back-blast to human, these do not quite pull up PCDH15 as best match but rather its closest paralog FAT4, perhaps because of lineage-specific expansion. Possibly CDH23 had not yet undergone duplication and divergence to protocadherins and it alone may play a doubled linker role in anemone stereocilia.

Nematocyst discharge is sensitive to calcium levels and streptomycin (like vertebrate mechanotransduction channels) but is insensitive to the MET channel blocker amiloride.

Prey capture can result in severe trauma to anemone tenacle hair bundles but this [can be repaired using a protein again with similarities to a vertebrate stereocilia repair protein ARL5B which acts on the extracellular face of the plasma membrane along stereocilia in the vicinity of tip links. Human and cnidarian protein XM_001629283 are 77% identical: 

homSap ARL5B  MGLIFAKLWSLFCNQEHKVIIVGLDNAGKTTILYQFLMNEVVHTSPTIGSNVEEIVVKNTFLMWDIGGQESLRSSWNTYYSNTEFIILV
              MGL+FAK +S F N+EHKVIIVGLDNAGKTTILYQFLMNEVVHTSPTIGSNVEEIV KNHF+MWDIGGQESLRS+WNTYY+NTEF+ILV 
nemVec repair MGLLFAKFFSWFSNEEHKVIIVGLDNAGKTTILYQFLMNEVVHTSPTIGSNVEEIVWKNIHFIMWDIGGQESLRSAWNTYYTNTEFLIL

homSap ARL5B  HVDSIDRERLAITKEELYRMLAHEDLRKAAVLIFANKQDMKGCMTAAEISKYLTLSSIKDHPWHIQSCCALTGEGLCQGLEWMTSRI
               +DS DRERLAI+K ELY+MLA+E+L++AA+ LI ANKQD+KG M+ AEIS+L L+ IKDH WHIQ+CCALTGEGL QGLEW+T+++
nemVec repair VIDSTDRERLAISKAELYQMLANEELKQAALLILANKQDIKGSMSVAEISEQLNLACIKDHGWHIQACCALTGEGLYQGLEWITTQL

Note 'stereocilia' is an anatomical misnomer. These are instead actin-based membrane protrusions. It is the kinocilium that is a true cilium in both anemone and developing vertebrate hair cells. If parallels to ciliary photoreceptors are sought, these should be with the kinocilium rather than stereocilia. Since no known counterpart to the PCDH15-CDH23 linker occurs in vision, the commonality (Usher syndrome) may reside primarily in ribbon synapses of auditory and photoreceptive neurons.

Pseudogene and paralog issues

No potential exists here for mis-determining orthologous exons, even in remote species such as lamprey with poor assemblies. Exceedingly long genes such as this are not well-represented as retrogenes (which begin 3' and truncate early). Position 1122 is too remote from the 3' terminus. Relevent pseudogenes are not observed by Blat of human, macaque, and dog. Indeed, this exon gives a unique match at this level of sensitivity, even though cadherins are very widespread in the proteome.

The top matches to CDH23 within the human genome are shown as provided by GeneSorter at UCSC. Observe the established binding partner PCDH15 is by no means the best match; the e-value is high but only because of many weak alignments of tandem cadherin domains.

PCDH15 has 11 cadherin domains and a transmembrane region C-terminally. It's problematic to call it a paralog of CDH23 even though all cadherin domains must ultimately coalesce. PCDH15 tandem domains, which cannot be put in 1:1 correspondence with the 27 cadherin domains of CDH23, might have had quite a different history of sources in its domain histories. The evolution of these gene families might be better worked out using interdomain spacer regions and intron position and phasing. Particular regions can be very conserved in themselves while not display much conservation between spacers.

Here the spacer region of CDH23 containing L1122 has best match within the human proteome to PCDHB14 (protocadherin beta 14), far down on the list of overall best matches. The interdomain region is shown in blue below. Note the best matches internally to other spacers are quite weak and neither L nor V is conserved in them. 

PCDH15   S-TLTLAIKVLDIDDNSPVFTNSTYTVLVEENLPAGTTILQIEAKDVDLG---ANVSYRIRS
         + | |+ + |||++|| |+|  |+|   | |++| | +|||++| | | |     | |||  
CDH23    TGTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQILKATDADEGEFGRVWYRILH  
         +GT  V + VLD+NDN P F QS YE  VPED P G  I  + A D D G +G++ Y   H
PCDHB14  SGTTLVLIKVLDINDNAPEFPQSLYEVQVPEDRPLGSWIATIISAKDLDAGNYGKISYTFFH

                           IFLQSSYEASVPEDIPEGHSILQLK 1122
                           TFQNLPFVAEVLEGIPAGVSIYQVV 928  CDH23 internal spacer
                           IFSQPLYNISLYENVTVGTSVLTVL 497  CDH23 internal spacer
                           TFFPAVYNVSVSEDVPREFRVVWLN 1034 CDH23 internal spacer
                           TFHNQPYSVRIPENTPVGTPIFIVN 169  CDH23 internal spacer
                           TWKDAPYYINLVEMTPPDSDVTTVV 809  CDH23 internal spacer

CDH23    0      chr10:72826710-73245710   cadherin-like 23
FAT4     0      chr4:126457017-126633537  FAT tumor suppressor homolog 4
DCHS1    0      chr11:6599134-6633650     dachsous 1
FAT3     0      chr11:91724910-92269283   FAT tumor suppressor homolog 3
FAT1     0      chr4:187745931-187881981  FAT tumor suppressor 1
FAT2     0      chr5:150863846-150928698  FAT tumor suppressor 2
DCHS2    0      chr4:155375138-155531899  dachsous 2 isoform 1
CELSR2  1e-115  chr1:109594164-109619901  cadherin EGF LAG seven-pass G-type receptor 2
CELSR1  5e-113  chr22:45135395-45311731   cadherin EGF LAG seven-pass G-type receptor 1
CELSR3  5e-109  chr3:48637835-48684985    cadherin EGF LAG seven-pass G-type receptor 3
PCDH24  3e-87   chr5:175908971-175955375  protocadherin LKC
...
PCDHB14  5e-53  chr5 140,584,653          protocadherin beta 14

Structural significance to normal function

Blastp at PDB of the region around residue L1122 establishes that the best fit to an already determined structure is the 39% identity match to mouse cadherin CDH8, 2A62. Within the 25 residue interdomain region, the percent identity is somewhat higher at nearly 50%. While not ideal, this should still allow accurate modeling of the adjacent cadherin domains and the critical spacer region, although the structural effects of the L1122V may be fairly subtle. 

CDH23  1    GTATVFVTVLDVNDNRPIFLQSSYEASVPEDIPEGHSILQLKATDADEGEFGRVWYRILHGNHGNNFRI
            GT T+ VT+ DVNDN P F QS Y  SVPED+  G +I ++KA D D GE  +  Y I+ G+    F I 
CDH8   174  GTTTLTVTLTDVNDNPPKFAQSLYHFSVPEDVVLGTAIGRVKANDQDIGENAQSSYDIIDGDGTALFEI
CDHe737v.jpg

Since CDH23 is known to form a helical homodimer in tip links -- and such binding patches can involve hydrophobic residues that otherwise would be buried -- the quaternary structure here is the main unknown. Crystallographic adjacency in the unit cell does not always reflect oligomeric solution structure. Consequently, it may not be possible to fully evaluate L1122V despite the favorable match at PDB.

There is no reason to think L1122V would directly affect the calcium binding motifs (LDRE, D.ND, D.D) of either adjacent cadherin domains in the manner of the E737V salsa mouse mutation in exon 22 or D124G, R1060W, E1595K and D2202N, none of which have syndromic effects on the retina but demonstrably weaken calcium dependent binding to PCDH15 even though they do not lie in the amino-terminal cadherin binding domains.

An effect of L1122V on the MET (mechanotransduction) channel is also implausibly indirect because this is at the lower (PCDH15) end of the link tip, though that is disputed for larger sound displacement effects.

Similarly an up-link intracellular effect of extracellular L1122V on CDH23 binding to harmonin would be a stretch. That binding is now thought mediated by an autonomously folding region proximal to the harmonin PDZ motif with a short internal peptide of CDH23 that extends from 3180-3211, KPDDDRYLRAAIQEYDNIAKLGQIIREGPIK, over 2,000 residues away.

The diagram below summarizes what is currently known about homotypic and heterotypic binding of proteins within the Usher network. Some of these remain unclear, like those of whirlin USH2D which also localizes at stereocilia tips and has an N-terminal domain like that of harmonin but yet does not bind CDH23. These interactions must be understood before SNPs such as V1122L can be modelled in their quaternary context and assessed with any confidence.
USHprots.jpg

Comparison of CDH15 domains to PCDH15

Given that CDH23 and PCDH15 binding constitutes the critical part of hair links joining a lower stereocilia to the next higher, it's worth investigating the evolutionary relationship betweeen the 27 and 11 cadherin ectodomains (ie the extent to which these proteins are paralogs and so naturally dimerize). It emerges that the cadherin domains have little residual sequence identity to each other within or across proteins, even though each individually has very considerable phylogenetic conservation.

Further, the cadherin domain of CDH23 best corresponding to a cadherin domain of PCDH15 (as linearly ordered in its primary sequence) are out of order with respect to the primary sequence of CDH23: 25, 16, 15, 13, 12, 16, 14, 2, 9, 18, 12. This suggests if a deep relationship ever existed between these two proteins, different rates of cadherin domain evolution has obscured it.

However when the 27 spacer domains separating cadherin units are concatenated, SMART detects an internal repeat within CDH23 of the first 11 to the last 11 spacers. Furthermore, these repeats give weak but full length alignments to the 11 concatenated spacer units of PCDH15. (Use of spacers avoids confounding issues of cadherin domain cross-matching.) This suggests the latter is ancestral length and that CDH23 experienced an internal duplication that lengthened its ectodomain. Spacers is surely a misnomer as the degree of phylogenetic conservation suggests each is under considerable selection along with its associated cadherin domains.

When the cytoplasmic domains are aligned (using uncorrected genomic alignments from the 46 species UCSC data set), it emerges that CDH23 (top) is far better conserved to far better phylogenetic depth than PCDH15 (bottom). This conservation does not extend into early deuterostomes, protostomes or cnidarians but rather emerged abruptly in lamprey (ie synchronoously with ciliary opsins and the retina).

Presumably both are specifically anchored to the internal Usher protein network at one or more domains, with the terminal PDZ binding motif ITEL* and STSL* respectively) and internal motif IM KPDDDRYLRAAIQEYDNIAKLGQIIREGPIK serving to anchor CDH23 but not PCDH15 bidentately to harmonin N-domain. However these domains can explain only a small fraction of observed CDH23 cytoplasmic conservation. Note runs of compositionally simple sequence cannot form ordered secondary or tertiary structure.

Intriguingly, whirlin (USH2D) has a similar domain structure to harmonin, in particular the N-domains align. Although this does not bind the cytoplasmic internal motif of CDH23, it could plausibly bind a comparable region in PCDH15, in effect quasi-paralog binding to quasi-paralog.

CadTails.jpg 

>CDH23_homSap domains: signal, 27 spacers, 27 cadhedrin domains (last weak), unknown extracellular, single pass transmembrane, unknown cytoplasmic: 
MGRHVATSCHVAWLLVLISGCWG
QVNRLPFFTNHFFDTYLLISEDTPVGSSVTQ
LLAQDMDNDPLVFGVSGEEASRFFAVEPDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITRKVNIQVGDVNDNAP
TFHNQPYSVRIPENTPVGTPIFI
VNATDPDLGAGGSVLYSFQPPSQFFAIDSARGIVTVIRELDYETTQAYQLTVNATDQDKTRPLSTLANLAIIITDVQDMDP
IFINLPYSTNIYEHSPPGTTVRI
ITAIDQDKGRPRGIGYTIVSGNTNSIFALDYISGVLTLNGLLDRENPLYSHGFILTVKGTELNDDRTPSDATVTTTFNILVIDINDNAP
EFNSSEYSVAITELAQVGFALPLF
IQVVDKDENLGLNSMFEVYLVGNNSHHFIISPTSVQGKADIRIRVAIPLDYETVDRYDFDLFANESVPDHVGYAKVKITLINENDNRP
IFSQPLYNISLYENVTVGTSVLT
VLATDNDAGTFGEVSYFFSDDPDRFSLDKDTGLIMLIARLDYELIQRFTLTIIARDGGGEETTGRVRINVLDVNDNVP
TFQKDAYVGALRENEPSVTQLVR
LRATDEDSPPNNQITYSIVSASAFGSYFDISLYEGYGVISVSRPLDYEQISNGLIYLTVMAMDAGNPPLNSTVPVTIEVFDENDNPP
TFSKPAYFVSVVENIMAGATVLF
LNATDLDRSREYGQESIIYSLEGSTQFRINARSGEITTTSLLDRETKSEYILIVRAVDGGVGHNQKTGIATVNITLLDINDNHP
TWKDAPYYINLVEMTPPDSDVTT
VVAVDPDLGENGTLVYSIQPPNKFYSLNSTTGKIRTTHAMLDRENPDPHEAELMRKIVVSVTDCGRPPLKATSSATVFVNLLDLNDNDP
TFQNLPFVAEVLEGIPAGVSIYQ
VVAIDLDEGLNGLVSYRMPVGMPRMDFLINSSSGVVVTTTELDRERIAEYQLRVVASDAGTPTKSSTSTLTIHVLDVNDETP
TFFPAVYNVSVSEDVPREFRVVW
LNCTDNDVGLNAELSYFITGGNVDGKFSVGYRDAVVRTVVGLDRETTAAYMLILEAIDNGPVGKRHTGTATVFVTVLDVNDNRP
IFLQSSYEASVPEDIPEGHSILQ
LKATDADEGEFGRVWYRILHGNHGNNFRIHVSNGLLMRGPRPLDRERNSSHVLIVEAYNHDLGPMRSSVRVIVYVEDINDEAP
VFTQQQYSRLGLRETAGIGTSVIV
VQATDRDSGDGGLVNYRILSGAEGKFEIDESTGLIITVNYLDYETKTSYMMNVSATDQAPPFNQGFCSVYITLLNELDEAV
QFSNASYEAAILENLALGTEIVR
VQAYSIDNLNQITYRFNAYTSTQAKALFKIDAITGVITVQGLVDREKGDFYTLTVVADDGGPKVDSTVKVYITVLDENDNSP
RFDFTSDSAVSIPEDCPVGQRVAT
VKAWDPDAGSNGQVVFSLASGNIAGAFEIVTTNDSIGEVFVARPLDREELDHYILQVVASDRGTPPRKKDHILQVTILDINDNPP
VIESPFGYNVSVNENVGGGTAVVQ
VRATDRDIGINSVLSYYITEGNKDMAFRMDRISGEIATRPAPPDRERQSFYHLVATVEDEGTPTLSATTHVYVTIVDENDNAP
MFQQPHYEVLLDEGPDTLNTSLIT
IQALDLDEGPNGTVTYAIVAGNIVNTFRIDRHMGVITAAKELDYEISHGRYTLIVTATDQCPILSHRLTSTTTVLVNVNDINDNVP
TFPRDYEGPFEVTEGQPGPRVWT
FLAHDRDSGPNGQVEYSIMDGDPLGEFVISPVEGVLRVRKDVELDRETIAFYNLTICARDRGMPPLSSTMLVGIRVLDINDNDP
VLLNLPMNITISENSPVSSFVAH
VLASDADSGCNARLTFNITAGNRERAFFINATTGIVTVNRPLDRERIPEYKLTISVKDNPENPRIARRDYDLLLIFLSDENDNHP
LFTKSTYQAEVMENSPAGTPLTVLNGP
ILALDADQDIYAVVTYQLLGAQSGLFDINSSTGVVTVRSGVIIDREAFSPPILELLLLAEDIGLLNSTAHLLITILDDNDNRP
TFSPATLTVHLLENCPPGFSVLQ
VTATDEDSGLNGELVYRIEAGAQDRFLIHLVTGVIRVGNATIDREEQESYRLTVVATDRGTVPLSGTAIVTILIDDINDSRP
EFLNPIQTVSVLESAEPGTVIAN
ITAIDHDLNPKLEYHIVGIVAKDDTDRLVPNQEDAFAVNINTGSVMVKSPMNRELVATYEVTLSVIDNASDLPERSVSVPNAKLTVNVLDVNDNTP
QFKPFGITYYMERILEGATPGTTLIA
VAAVDPDKGLNGLVTYTLLDLVPPGYVQLEDSSAGKVIANRTVDYEEVHWLNFTVRASDNGSPPRAAEIPVYLEIVDINDNNP
IFDQPSYQEAVFEDVPVGTIILT
VTATDADSGNFALIEYSLGDGESKFAINPTTGDIYVLSSLDREKKDHYILTALAKDNPGDVASNRRENSVQVVIQVLDVNDCRP
QFSKPQFSTSVYENEPAGTSVIT
MMATDQDEGPNGELTYSLEGPGVEAFHVDMDSGLVTTQRPLQSYEKFSLTVVATDGGEPPLWGTTMLLVEVIDVNDNRP
VFVRPPNGTILHIREEIPLRSNVYE
VYATDKDEGLNGAVRYSFLKTAGNRDWEFFIIDPISGLIQTAQRLDRESQAVYSLILVASDLGQPVPYETMQPLQVALEDIDDNEP
LFVRPPKGSPQYQLLTVPEHSPRGTLVGNV
TGAVDADEGPNAIVYYFIAAGNEEKNFHLQPDGCLLVLRDLDREREAIFSFIVKASSNRSWTPPRGPSPTLDLVADLTLQEVRVVLEDINDQPP
RFTKAEYTAGVATDAKVGSELIQ
VLALDADIGNNSLVFYSILAIHYFRALANDSEDVGQVFTMGSMDGILRTFDLFMAYSPGYFVVDIVARDLAGHNDTAIIGIYILRDDQRV
KIVINEIPDRVRGFEEEFIHLLSNITGAIVNTDNVQFHVDKKGRVNFAQTELLIHVVNRDTNRILDVDRVIQMIDENKEQLRNLFRNYNVLDVQPAISVRLPDDMSALQM
AIIVLAILLFLAAMLFVLMNWYY
RTVHKRKLKAIVAGSAGNRGFIDIMDMPNTNKYSFDGANPVWLDPFCRNLELAAQAEHEDDLPENLSEIADLWNSPTRTHGTFGREPAAVKPDDDRYLRAAIQEYDNIAKLGQIIREGPIKGSLLKVVLEDYLRLKKLFAQRMVQKASSCHSSISELIQTELDEEPGDHSPGQGSLRFRHKPPVELKGPDGIHVVHGSTGTLLATDLNSLPEEDQKGLGRSLETLTAAEATAFERNARTESAKSTPLHKLRDVIMETPLEITEL

>PCDH15_homSap domains: signal, 11 spacers, 11 cadhedrin domains, unknown extracellular, single pass transmembrane, unknown cytoplasmic: 
MFRQFYLWTCLASGIILGSLFEICLG
QYDDDCKLARGGPPATIVAIDEESRNGTILVDNMLIK
GTAGGPDPTIELSLKDNVDYWVLMDPVKQMLFLNSTGRVLDRDPPMNIHSIVVQVQCINKKVGTIIYHEVRIVVRDRNDNSP
TFKHESYYATVNELTPVGTTIFTGFSGD
NGATDIDDGPNGQIEYVIQYNPDDPTSNDTFEIPLMLTGNIVLRKRLNYEDKTRYFVIIQANDRAQNLNERRTTTTTLTVDVLDGDDLGP
MFLPCVLVPNTRDCRPLTYQAAIPELRTPEELNPIIVTPP
IQAIDQDRNIQPPSDRPGILYSILVGTPEDYPRFFHMHPRTAELSLLEPVNRDFHQKFDLVIKAEQDNGHPLPAFAGLHIEILDENNQSP
YFTMPSYQGYILESAPVGATISDSLNLTSPLR
IVALDKDIEDTKDPELHLFLNDYTSVFTVTQTGITRYLTLLQPVDREEQQTYTFSITAFDGVQESEPVIVNIQVMDANDNTP
TFPEISYDVYVYTDMRPGDSVIQ
LTAVDADEGSNGEITYEILVGAQGDFIINKTTGLITIAPGVEMIVGRTYALTVQAADNAPPAERRNSICTVYIEVLPPNNQSP
PRFPQLMYSLEISEAMRVGAVLLN
LQATDREGDSITYAIENGDPQRVFNLSETTGILTLGKALDRESTDRYILIITASDGRPDGTSTATVNIVVTDVNDNAP
VFDPYLPRNLSVVEEEANAFVGQ
VKATDPDAGINGQVHYSLGNFNNLFRITSNGSIYTAVKLNREVRDYYELVVVATDGAVHPRHSTLTLAIKVLDIDDNSP
VFTNSTYTVLVEENLPAGTTILQ
IEAKDVDLGANVSYRIRSPEVKHFFALHPFTGELSLLRSLDYEAFPDQEASITFLVEAFDIYGTMPPGIATVTVIVKDMNDYPP
VFSKRIYKGMVAPDAVKGTPITT
VYAEDADPPGLPASRVRYRVDDVQFPYPASIFEVEEDSGRVITRVNLNEEPTTIFKLVVVAFDDGEPVMSSSATVKILVLHPGEIPR
FTQEEYRPPPVSELATKGTM
VGVISAAAINQSIVYSIVSGNEEDTFGINNITGVIYVNGPLDYETRTSYVLRVQADSLEVVLANLRVPSKSNTAKVYIEIQDENNHPP
VFQKKFYIGGVSEDARMFTSVLR
VKATDKDTGNYSVMAYRLIIPPIKEGKEGFVVETYTGLIKTAMLFHNMRRSYFKFQVIATDDYGKGLSGKADVLVSVVNQLDMQV
IVSNVPPTLVEKKIEDLTEILDRYVQEQIPGAKVVVESIGARRHGDAFSLEDYTKCDLTVYAIDPQTNRAIDRNELFKFLDGKLLDINKDFQPYYGEGGRILEIRTPEAVTSIKKRGESLGYTE
GALLALAFIIILCCIPAILVVLV
SYRQFKVRQAECTKTARIQAALPAAKPAVPAPAPVAAPPPPPPPPPGAHLYEELGDSSILFLLYHFQQSRGNNSVSEDRKHQQVVMPFSSNTIEAHKSAHVDGSLKSNKLKSARKFTFLSDEDDLSAHNPLYKENISQVSTNSDISQRTDFVDPFSPKIQAKSKSLRGPREKIQRLWSQSVSLPRRLMRKVPNRPEIIDLQQWQGTRQKAENENTGICTNKRGSSNPLLTTEEANLTEKEEIRQGETLMIEGTEQLKSLSSDSSFCFPRPHFSFSTLPTVSRTVELKSEPNVISSPAECSLELSPSRPCVLHSSLSRRETPICMLPIETERNIFENFAHPPNISPSACPLPPPPPISPPSPPPAPAPLAPPPDISPFSLFCPPPSPPSIPLPLPPPTFFPLSVSTSGPPTPPLLPPFPTPLPPPPPSIPCPPPPSASFLSTECVCITGVKCTTNLMPAEKIKSSMTQLSTTTVCKTDPQREPKGILRHVKNLAELEKSVANMYSQIEKNYLRTNVSELQTMCPSEVTNMEITSEQNKGSLNNIVEGTEKQSHSQSTSL 

Numbered cadhedrin domains of CDH23

>CDH23.CA.01
LLAQDMDNDPLVFGVSGEEASRFFAVEPDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITRKVNIQVGDVNDNAP
>CDH23.CA.02
VNATDPDLGAGGSVLYSFQPPSQFFAIDSARGIVTVIRELDYETTQAYQLTVNATDQDKTRPLSTLANLAIIITDVQDMDP
>CDH23.CA.03
ITAIDQDKGRPRGIGYTIVSGNTNSIFALDYISGVLTLNGLLDRENPLYSHGFILTVKGTELNDDRTPSDATVTTTFNILVIDINDNAP
>CDH23.CA.04
IQVVDKDENLGLNSMFEVYLVGNNSHHFIISPTSVQGKADIRIRVAIPLDYETVDRYDFDLFANESVPDHVGYAKVKITLINENDNRP
>CDH23.CA.05
VLATDNDAGTFGEVSYFFSDDPDRFSLDKDTGLIMLIARLDYELIQRFTLTIIARDGGGEETTGRVRINVLDVNDNVP
>CDH23.CA.06
LRATDEDSPPNNQITYSIVSASAFGSYFDISLYEGYGVISVSRPLDYEQISNGLIYLTVMAMDAGNPPLNSTVPVTIEVFDENDNPP
>CDH23.CA.07
LNATDLDRSREYGQESIIYSLEGSTQFRINARSGEITTTSLLDRETKSEYILIVRAVDGGVGHNQKTGIATVNITLLDINDNHP
>CDH23.CA.08
VVAVDPDLGENGTLVYSIQPPNKFYSLNSTTGKIRTTHAMLDRENPDPHEAELMRKIVVSVTDCGRPPLKATSSATVFVNLLDLNDNDP
>CDH23.CA.09
VVAIDLDEGLNGLVSYRMPVGMPRMDFLINSSSGVVVTTTELDRERIAEYQLRVVASDAGTPTKSSTSTLTIHVLDVNDETP
>CDH23.CA.10
LNCTDNDVGLNAELSYFITGGNVDGKFSVGYRDAVVRTVVGLDRETTAAYMLILEAIDNGPVGKRHTGTATVFVTVLDVNDNRP
>CDH23.CA.11
LKATDADEGEFGRVWYRILHGNHGNNFRIHVSNGLLMRGPRPLDRERNSSHVLIVEAYNHDLGPMRSSVRVIVYVEDINDEAP
>CDH23.CA.12
VQATDRDSGDGGLVNYRILSGAEGKFEIDESTGLIITVNYLDYETKTSYMMNVSATDQAPPFNQGFCSVYITLLNELDEAV
>CDH23.CA.13
VQAYSIDNLNQITYRFNAYTSTQAKALFKIDAITGVITVQGLVDREKGDFYTLTVVADDGGPKVDSTVKVYITVLDENDNSP
>CDH23.CA.14
VKAWDPDAGSNGQVVFSLASGNIAGAFEIVTTNDSIGEVFVARPLDREELDHYILQVVASDRGTPPRKKDHILQVTILDINDNPP
>CDH23.CA.15
VRATDRDIGINSVLSYYITEGNKDMAFRMDRISGEIATRPAPPDRERQSFYHLVATVEDEGTPTLSATTHVYVTIVDENDNAP
>CDH23.CA.16
IQALDLDEGPNGTVTYAIVAGNIVNTFRIDRHMGVITAAKELDYEISHGRYTLIVTATDQCPILSHRLTSTTTVLVNVNDINDNVP
>CDH23.CA.17
FLAHDRDSGPNGQVEYSIMDGDPLGEFVISPVEGVLRVRKDVELDRETIAFYNLTICARDRGMPPLSSTMLVGIRVLDINDNDP
>CDH23.CA.18
VLASDADSGCNARLTFNITAGNRERAFFINATTGIVTVNRPLDRERIPEYKLTISVKDNPENPRIARRDYDLLLIFLSDENDNHP
>CDH23.CA.19
ILALDADQDIYAVVTYQLLGAQSGLFDINSSTGVVTVRSGVIIDREAFSPPILELLLLAEDIGLLNSTAHLLITILDDNDNRP
>CDH23.CA.20
VTATDEDSGLNGELVYRIEAGAQDRFLIHLVTGVIRVGNATIDREEQESYRLTVVATDRGTVPLSGTAIVTILIDDINDSRP
>CDH23.CA.21
ITAIDHDLNPKLEYHIVGIVAKDDTDRLVPNQEDAFAVNINTGSVMVKSPMNRELVATYEVTLSVIDNASDLPERSVSVPNAKLTVNVLDVNDNTP
>CDH23.CA.22
VAAVDPDKGLNGLVTYTLLDLVPPGYVQLEDSSAGKVIANRTVDYEEVHWLNFTVRASDNGSPPRAAEIPVYLEIVDINDNNP
>CDH23.CA.23
VTATDADSGNFALIEYSLGDGESKFAINPTTGDIYVLSSLDREKKDHYILTALAKDNPGDVASNRRENSVQVVIQVLDVNDCRP
>CDH23.CA.24
MMATDQDEGPNGELTYSLEGPGVEAFHVDMDSGLVTTQRPLQSYEKFSLTVVATDGGEPPLWGTTMLLVEVIDVNDNRP
>CDH23.CA.25
VYATDKDEGLNGAVRYSFLKTAGNRDWEFFIIDPISGLIQTAQRLDRESQAVYSLILVASDLGQPVPYETMQPLQVALEDIDDNEP
>CDH23.CA.26
TGAVDADEGPNAIVYYFIAAGNEEKNFHLQPDGCLLVLRDLDREREAIFSFIVKASSNRSWTPPRGPSPTLDLVADLTLQEVRVVLEDINDQPP
>CDH23.CA.27 weak
VLALDADIGNNSLVFYSILAIHYFRALANDSEDVGQVFTMGSMDGILRTFDLFMAYSPGYFVVDIVARDLAGHNDTAIIGIYILRDDQRV

Numbered cadhedrin domains of PCDH15 with individual best blastp to a CDH23 cadhedrin domain

>PCDH15.CA.01 CDH23.CA.25 
GTAGGPDPTIELSLKDNVDYWVLMDPVKQMLFLNSTGRVLDRDPPMNIHSIVVQVQCINKKVGTIIYHEVRIVVRDRNDNSP
>PCDH15.CA.02 CDH23.CA.16 
NGATDIDDGPNGQIEYVIQYNPDDPTSNDTFEIPLMLTGNIVLRKRLNYEDKTRYFVIIQANDRAQNLNERRTTTTTLTVDVLDGDDLGP
>PCDH15.CA.03 CDH23.CA.15 
IQAIDQDRNIQPPSDRPGILYSILVGTPEDYPRFFHMHPRTAELSLLEPVNRDFHQKFDLVIKAEQDNGHPLPAFAGLHIEILDENNQSP
>PCDH15.CA.04 CDH23.CA.13
IVALDKDIEDTKDPELHLFLNDYTSVFTVTQTGITRYLTLLQPVDREEQQTYTFSITAFDGVQESEPVIVNIQVMDANDNTP
>PCDH15.CA.05 CDH23.CA.12  
LTAVDADEGSNGEITYEILVGAQGDFIINKTTGLITIAPGVEMIVGRTYALTVQAADNAPPAERRNSICTVYIEVLPPNNQSP
>PCDH15.CA.06 CDH23.CA.16 
LQATDREGDSITYAIENGDPQRVFNLSETTGILTLGKALDRESTDRYILIITASDGRPDGTSTATVNIVVTDVNDNAP
>PCDH15.CA.07 CDH23.CA.14 
VKATDPDAGINGQVHYSLGNFNNLFRITSNGSIYTAVKLNREVRDYYELVVVATDGAVHPRHSTLTLAIKVLDIDDNSP
>PCDH15.CA.08 CDH23.CA.02
IEAKDVDLGANVSYRIRSPEVKHFFALHPFTGELSLLRSLDYEAFPDQEASITFLVEAFDIYGTMPPGIATVTVIVKDMNDYPP
>PCDH15.CA.09 CDH23.CA.09
VYAEDADPPGLPASRVRYRVDDVQFPYPASIFEVEEDSGRVITRVNLNEEPTTIFKLVVVAFDDGEPVMSSSATVKILVLHPGEIPR
>PCDH15.CA.10 CDH23.CA.18
VGVISAAAINQSIVYSIVSGNEEDTFGINNITGVIYVNGPLDYETRTSYVLRVQADSLEVVLANLRVPSKSNTAKVYIEIQDENNHPP
>PCDH15.CA.11 CDH23.CA.12
VKATDKDTGNYSVMAYRLIIPPIKEGKEGFVVETYTGLIKTAMLFHNMRRSYFKFQVIATDDYGKGLSGKADVLVSVVNQLDMQV

Difference alignment of human CDH23 cadherin domains

CDH23.CA.01  LLAQDMDN----------DPLVFGVSGEEASRFFAVEP--DTGVVWLRQ----PL------DRETKSEFTVEFSVSDH--QGVITRKVNIQVGDVNDNAP
CDH23.CA.02  VN.T.P.LGAG------GSV.YSFQPPS-----QFFAIDSAR.I.TVIRELDYET----TQAYQLTVNA.DQ---DKTRPLST-LANLA.IIT..Q.MD.
CDH23.CA.03  IT.I.Q.KGRP------RGIGYTI...NTN.---IFALDYIS..L-TLNGLLDRENPLYSHGFILT-VKGT.LNDDRTPSDATV.TTF..L.I.I.....
CDH23.CA.04  IQVV.K.ENLG------LNSMFEVYLVGNN.HH.IIS.TSVQ.KADI.IRVAI..------.Y..VDRYDFDLFANESVPDH.GYA..K.TLINE...R.
CDH23.CA.05  V..T.N.AGTF------GEVSY.FSDDPDR-----FSLDK...LIM.IARLDYE.----IQRFTLTIIARDG---G---GEET-.GR.R.N.L.....V.
CDH23.CA.06  .R.T.E.SPPN------NQITYSI..ASAFGSY.DISLYEGY..ISVSRPLDYEQ-----ISNGLIYLTVMAMDAGNPP--LNS.VP.T.E.F.E...P.
CDH23.CA.07  .N.T.L.RSRE------YGQESIIY.L.GST---QFRINARS.EITTTSLLDRET----KSEYILIVRAVDG--GVG.NQKTG-IAT...TLL.I...H.
CDH23.CA.08  VV.V.P.LGEN------GTLVYSIQPPN--K---FYSLNST..KIRTTHAMLDRENPDPHEAELMRKIVVSVTDCGRPPLKATSSAT.FVNLL.L...D.
CDH23.CA.09  VV.I.L.EGLN------GLVSYRMPV.MPRM---DFLINSSS..--VVTTTELDR-----ERIAEYQLRV.ASDAGTPT--KSS.STLT.H.L....ET.
CDH23.CA.10  .NCT.N.VGLN------AELSY.ITG.NVDG---KFSVGYRDA..RTVVGLDRET----TAAYMLIL.AIDN--GPVGKRHTG-.AT.FVT.L.....R.
CDH23.CA.11  .K.T.A.EGEF------GRVWYRILH.NHGN---NFRIHVSN.LLMRGPRP-LDR-----ERNSSHVLIVEAYNHDLGP--MRSSVR.IVY.E.I..E..
CDH23.CA.12  VQ.T.R.SGDG------GLVNYRIL..A.GK----F.IDES..LIITVNYLDYET----KTSYMMNVSA.DQ---APPFN..F-CSVYITLLNELDEAV 
CDH23.CA.13  VQ.YSI..LNQ------ITYRFNAYTSTQ.KAL.KID--AI...ITVQGLV----------...KGDFY.LTVVAD.GGPKVDS.V..Y.T.L.E...S.
CDH23.CA.14  VK.W.P.AGSN------GQVVFSLA..NI.GA.EI.TTNDSI.E.FVARPLDREE-----L.HYI--LQV.ASDRGTPP--RKKDHILQVTIL.I...P.
CDH23.CA.15  VR.T.R.IGIN------SVLSYYITE.NKDM---.FRMDRIS.EIAT.PAP-PDR-----ERQSFYHLVATVEDEGTPT--LSA.TH.YVTIV.E.....
CDH23.CA.16  IQ.L.L.EGPN------GTVTYAI.A.NIVN---TFRIDRHM..I-TAAKELDYE---ISHG.Y.L-IV.ATDQCPILSHRLTS.TT.LVN.N.I...V.
CDH23.CA.17  F..H.R.SGPN------GQVEYSIMD.DPLG---EFVISPVE..LRV.KDVELDR-----ETIAFYNLTICARDRGMPP--LSS.ML.G.R.L.I...D.
CDH23.CA.18  V..S.A.SGCN------ARLTFNITA.NRER---.FFINAT..I.TVNRPLDRER----IPEYKLTISVKDNPENPRIARRDY-DL-LL.FLS.E...H.
CDH23.CA.19  I..L.A.QDIY------AVVTYQLL-.AQSG---LFDINSS....TV.SGVIIDR-----EAFSPPILELLLLAEDIGL--LNS.AHLL.TIL.D...R.
CDH23.CA.20  VT.T.E.SGLN------GELVYRIEA.-AQD---RFLIHLV...IRVGNAT-IDR-----EEQ.SYRLTV.ATDRGTVP--LSG.AI.T.LID.I..SR.
CDH23.CA.21  IT.I.H.LNPKLEYHIVGIVAKDDTDRLVPNQED.FAVNIN..S.MVKSPMNRE.----VATY.VTLSVIDNA.DLPERSVS.PNA.LTVN.L.....T.
CDH23.CA.22  VA.V.P.KGLN------GLVTYTLLDLVPPG--YVQLEDSSA.K.IANRTVDYEE-----V-HWL-NFTVRASDNGSPP--RAAEIP.YLEIV.I...N.
CDH23.CA.23  VT.T.A.SGNF------ALIEYSL--.DGE.---KFAINPT..DIYVLSSLDREK----KDHYILTALAKDNPGDVASNRREN-SVQ.V...L....CR.
CDH23.CA.24  MM.T.Q.EGPN------GELTYSLEGPGV----E.FHVDM.S.L.TTQRPLQSYE-----KFS----LTV.ATDGGEPP--LWG.TMLLVE.I.....R.
CDH23.CA.25  VY.T.K.EGLN------GAVRYSFLKTAGNRDWEFFIIDPIS.LIQTA.RLDRES----QAVYSLILVASDL---GQPVPYET-MQPLQVALE.ID..E.
CDH23.CA.26  TG.V.A.EGPN------AIVYY.IAA.N.EKN.HLQPDGCLLVLRD.DREREAIFSFIVKASSNRSWTPPRGP.PTLDLVADLTLQE.RVVLE.I..QP.
CDH23.CA.27  V..L.A.IGNN------SLVFYSILAIHYFRALANDSEDVGQVFT-MGSMDGILRTFDLFMAYSPGYFVVDIVARDLAGHNDTAIIGIY.LRD.QRV   
 Consensus   !.......G.n      g.v.Y.i..g........f........!..........    ............................v.!..........

Difference alignment of human CDH23 cadherin domains

PCDH15.CA.01           GTAGGPDPTIELSLKDN---VDYWVLMDPVKQMLFLNSTGRVLDRDPPMNIHSIV-----VQVQCINKKVGTIIYHEVRIVVRDRNDNSP
PCDH15.CA.02       NGATDIDD..NGQ..YVIQY.PDDPTSNDTFEIPLMLTGNIVLRKR.NYEDKTRYFV.I----QANDRAQ.LNERRTTTTTLTVD.L.GD.LG.
PCDH15.CA.07       VKATDPDA.INGQVHY..G------NFNN.FRITS--NGSIY.AVK.N.EVRDYYELV.----VATDGAVH---PRHSTLTLA.K.L.ID....
PCDH15.CA.05       LTAVDADE.SNGE.TYEILV-----GAQGDFIIN.T-TG.ITIAPGVEMIVGRTYALT.----QAADNAPPA-ERRNSICT.Y.E.LPP.NQ..
PCDH15.CA.06          LQATDREGDS.TYAIEN----G.PQRVFNLSET-TGILTL.KA...ESTDRYIL--------IITASDGRPDGTSTAT.N...T.V...A.
PCDH15.CA.10        VGVIS.AAINQS.VY.IVS----GNEEDTFGINNI-TGVIYVNGP..YETRTSYVLR.QADSLEV.LANLRVPSKSNTAK.Y.EIQ.E.NHP.
PCDH15.CA.08         IEAKDVDLGANVSYRIRS----PEVKHFFALHPF-TGEL.LL.S..YEAFPDQEASI---TFLVEAFDIYGTMPPGIAT.TVI.K.M..YP.
PCDH15.CA.03  IQAIDQDRNIQPPSDR.G.LY.ILVGTPEDYPRFFHMHPR--TAEL.LLEPVN..FHQKFDLVI-------KAEQDNGHPLPAFAGLH.EIL.E.NQ..
PCDH15.CA.04    IVALDKDIEDTKDPELHLFL------NDYTS.FTVTQTGITRYLTLLQPV..EEQQTYTFSI-------TAFDGVQESEPVI--.N.Q.M.A...T.
PCDH15.CA.09    VYAEDAD-PP.L.ASRVRYRVD.VQFPYPASIFEVEED--SGRVI.RVN.NEE.TTIFKLV.-------.AFDDGEPVMSSSAT.K.L.LHPGEIPR
PCDH15.CA.11    VKATDKD-.GNY--SVMAYR.IIPPIKEGKEGFVVETY--TG.IK.AMLFHNMRRSYFKFQ.-------IATDDYGK.LSGKAD.LVS.VNQL.MQV
 Consensus      .........d......!.Y.i...........ff..... TG.i.l...l#r#....%.l.!    ....aa..........at.....l..##...

>CDH23_spacers color shows repeat detected by SMART
QVNRLPFFTNHFFDTYLLISEDTPVGSSVTQ
TFHNQPYSVRIPENTPVGTPIFI
IFINLPYSTNIYEHSPPGTTVRI
EFNSSEYSVAITELAQVGFALPLF
IFSQPLYNISLYENVTVGTSVLT
TFQKDAYVGALRENEPSVTQLVR
TFSKPAYFVSVVENIMAGATVLF
TWKDAPYYINLVEMTPPDSDVTT
TFQNLPFVAEVLEGIPAGVSIYQ
TFFPAVYNVSVSEDVPREFRVVW
IFLQSSYEASVPEDIPEGHSILQ
VFTQQQYSRLGLRETAGIGTSVIV
QFSNASYEAAILENLALGTEIVR
RFDFTSDSAVSIPEDCPVGQRVAT
VIESPFGYNVSVNENVGGGTAVVQ
MFQQPHYEVLLDEGPDTLNTSLIT
TFPRDYEGPFEVTEGQPGPRVWT
VLLNLPMNITISENSPVSSFVAH
LFTKSTYQAEVMENSPAGTPLTVLNGP
TFSPATLTVHLLENCPPGFSVLQ
EFLNPIQTVSVLESAEPGTVIAN
QFKPFGITYYMERILEGATPGTTLIA
IFDQPSYQEAVFEDVPVGTIILT
QFSKPQFSTSVYENEPAGTSVIT
VFVRPPNGTILHIREEIPLRSNVYE
LFVRPPKGSPQYQLLTVPEHSPRGTLVGNV
RFTKAEYTAGVATDAKVGSELIQ

>PCDH15_spacers color shows 26% identity alignment to CDH23 spacer repeat
QYDDDCKLARGGPPATIVAIDEESRNGTILVDNMLIK
TFKHESYYATVNELTPVGTTIFTGFSGD
MFLPCVLVPNTRDCRPLTYQAAIPELRTPEELNPIIVTPP
YFTMPSYQGYILESAPVGATISDSLNLTSPLR
TFPEISYDVYVYTDMRPGDSVIQ
PRFPQLMYSLEISEAMRVGAVLLN
VFDPYLPRNLSVVEEEANAFVGQ
VFTNSTYTVLVEENLPAGTTILQ
VFSKRIYKGMVAPDAVKGTPITT
FTQEEYRPPPVSELATKGTM
VFQKKFYIGGVSEDARMFTSVLR

CDH23 allele assessment by PolyPhen

Here L1122V will test out as benign because it is a common conservative substitution and comparative genomics support in fish. PolyPhen and SIFT have comparative genomics limited to sequences at SwissProt and do not incorporate phylogenetic relations; consequently they miss the L-->V transition at the level of the tetrapod clade. Consequently such tools do not utilize a significant part of the available information and are not informative here.

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