USH2A SNPs
USH2A
Usherin (USH2A), a 71-exon coding gene located on human chromosome 1q41], encodes a 5202 residue multi-domain protein comprised of a signal peptide, a PDZ1 binding domain (for USH1C and WHRN), 1 laminin NT-terminal domain, 10 laminin EGF-like domains, 4 fibronectin type-III domains (for collagen IV and fibronectin), and 2 laminin G-like domains followed by 31 additional fibronectin type-III domains all tethered to the cytoplasmic exterior by a single transmembrane domain.
The usherin gene is expressed in the basement membrane of many (but not all) cell types, notably in ear interstereocilia ankles and below retinal pigment epithelial cells (Bruch's layer). When normal function is disrupted by mutations in both copies, non-vestibular sensorineural deafness and degeneration of retinal photoreceptor cells called Usher syndrome type IIA results.
Initially, only the first 21 exons were studied but later it emerged that the gene was much longer and mutations along the entire length of the protein all led to the same disease: 125, 163, 230, 268, 303, 334, 346, 352, 478, 536, 595, 644, 713, 759, 1212, 1349, 1486, 1572, 1665, 1757, 2080, 2086, 2106, 2169, 2238, 2265, 2266, 2292, 2562, 2875, 2886, 3088, 3099, 3115, 3124, 3144, 3199, 3411, 3504, 3521, 3590, 3835, 3868, 3893, 4054, 4115, 4232, 4433, 4439, 4487, 4592, 4624, 4795, 5031.
This note evaluates a tentative new SNP in USH2A with comparative genomics. The mutation occurs as a non-hotspot G-->A transition causing a seemingly innoculous S-->N amino acid change at postion 3743. This residue lies in the 22nd fibronectin domain which is split across exon 34 and 35.
This change will be shown significant (not plausibly neutral). It could represent an innovation but is more likely deleterious. The gene is single-copy so there are no prospects for compensation by a second gene. Consequently the mutation, if present on both alleles, could well result in a new form of Usher syndrome type IIA.
Background
Fibronectin FN3 domains are an ancient and exceedingly common domain in bilaterans with 2% of the human proteome containing them (400 genes), often in multiple tandem copies having a role in cell adhesion.
Pseudogene issues
Paralog issues
Known variations
Side issues
Structural significance
Functional significance
Comparative genomics
USH2A_homSap USH2A_panTro USH2A_gorGor USH2A_ponAbe USH2A_rheMac USH2A_calJac USH2A_micMur USH2A_otoGar USH2A_tupBel USH2A_musMus USH2A_ratNor USH2A_criGri USH2A_dipOrd USH2A_cavPor USH2A_speTri USH2A_oryCun USH2A_ochPri USH2A_vicPac USH2A_susScr USH2A_turTru USH2A_bosTau USH2A_equCab USH2A_felCat USH2A_canFam USH2A_myoLuc USH2A_eriEur USH2A_sorAra USH2A_loxAfr USH2A_proCap USH2A_echTel USH2A_monDom USH2A_macEug USH2A_sarHar1 USH2A_ornAna USH2A_galGal USH2A_taeGut USH2A_anoCar USH2A_xenTro USH2A_tetNig USH2A_takRub USH2A_gasAcu USH2A_oryLat USH2A_danRer USH2A_oncMyk USH2A_pimPro USH2A_calMil USH2A_petMar USH2A_braFlo USH2A_strPur USH2A_helRob USH2A_nemVec
