UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes

Abstract

Using the Universal Mutation Database (UMD) software, we have constructed "UMD-USHbases", a set of relational databases of nucleotide variations for seven genes involved in Usher syndrome (MYO7A, CDH23, PCDH15, USH1C, USH1G, USH3A and USH2A). Mutations in the Usher syndrome type I causing genes are also recorded in non-syndromic hearing loss cases and mutations in USH2A in non-syndromic retinitis pigmentosa. Usher syndrome provides a particular challenge for molecular diagnostics because of the clinical and molecular heterogeneity. As many mutations are missense changes, and all the genes also contain apparently non-pathogenic polymorphisms, well-curated databases are crucial for accurate interpretation of pathogenicity. Tools are provided to assess the pathogenicity of mutations, including conservation of amino acids and analysis of splice-sites. Reference amino acid alignments are provided. Apparently non-pathogenic variants in patients with Usher syndrome, at both the nucleotide and amino acid level, are included. The UMD-USHbases currently contain more than 2,830 entries including disease causing mutations, unclassified variants or non-pathogenic polymorphisms identified in over 938 patients. In addition to data collected from 89 publications, 15 novel mutations identified in our laboratory are recorded in MYO7A (6), CDH23 (8), or PCDH15 (1) genes. Information is given on the relative involvement of the seven genes, the number and distribution of variants in each gene. UMD-USHbases give access to a software package that provides specific routines and optimized multicriteria research and sorting tools. These databases should assist clinicians and geneticists seeking information about mutations responsible for Usher syndrome.

Mutation analysis of the MYO7A and CDH23 genes in Japanese patients with Usher syndrome type 1

“…12,21,26 All of these mutations occurred by transition (C/G-T/A) at CpG sites and were considered to be recurrent, which meets the fact that they are not specific to a particular ethnic group. This finding is consistent with a result of an analysis by Baux et al, 27 who reported that a high proportion of MYO7A and CDH23 mutations are represented by single base-pair substitutions and that 51.5 and 48.5% of them in MYO7A and CDH23, respectively, involve a CpG dinucleotide. Interestingly, neither of the two novel mutations found in the present study is of the transition type.…”

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

“…Mutations that lead to predicted CDH23 null alleles cause USH1D (Fig. 2D) (1)(2)(3)(4)(5)(7)(8)(9)(10)(11)(12), which is modeled by mutations in waltzer mice (Fig. 2D) (27,33,34).…”

“…The cadherin 23 gene (CDH23) provides a striking example. Predicted CDH23 null mutations lead to deaf-blindness (USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). A polymorphism in Cdh23 is linked to age-related hearing loss (14).…”

The USH2A c.2299delG mutation: dating its common origin in a Southern European population

“…A great majority of these mutations are private or present in a few families. 14 However, a prevalent mutation located in exon 13, designated as c.2299delG, is frequently found in the European and US patients, and also in isolated cases from South America, South Africa and Asia. The allele frequency distribution of c.2299delG varies geographically in Europe.…”