Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II

Department of Otolaryngology, University of Miami, Miami, FL 33136, USA.
Journal of Human Genetics (Impact Factor: 2.46). 10/2009; 54(12):732-8. DOI: 10.1038/jhg.2009.107
Source: PubMed


Usher syndrome type II (USH2) is an autosomal recessive disorder characterized by moderate to severe hearing impairment and progressive visual loss due to retinitis pigmentosa (RP). To identify novel mutations and determine the frequency of USH2A mutations as a cause of USH2, we have carried out mutation screening of all 72 coding exons and exon-intron splice sites of the USH2A gene. A total of 20 USH2 American probands of European descent were analyzed using single strand conformational polymorphism (SSCP) and direct sequencing methods. Ten different USH2A mutations were identified in 55% of the probands, five of which were novel mutations. The detected mutations include three missense, three frameshifts and four nonsense mutations, with c.2299delG/p.E767fs mutation, accounting for 38.9% of the pathological alleles. Two cases were homozygotes, two cases were compound heterozygotes and one case had complex allele with three variants. In seven probands, only one USH2A mutation was detected and no pathological mutation was found in the remaining eight individuals. Altogether, our data support the fact that c.2299delG/p.E767fs is indeed the most common USH2A mutation found in USH2 patients of European Caucasian background. Thus, if screening for mutations in USH2A is considered, it is reasonable to screen for the c.2299delG mutation first.

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    • "Both residues Ala457 and Lys269 are located within the myosin head-like domain, and of note, the location of p.Ala457Val is quite close to that of mutation p.Ser448Argfs*18 identified in our study, which could possibly explain for the USH type 2 phenotypes they caused. USH type 2 are associated with three genes, namely USH2A, GPR98, and DFNB31, implying the potentially complicated genotype-phenotype correlations for USH type 2. Mutations in USH2A account for over 70% of cases affected with USH type 2. In particular, many patients carrying mutations in USH2A showed moderate to severe SNHL with no vestibular defects and progressive retinitis pigmentosa [15], [59], all of which are very similar to the phenotypes observed in the present family USH01, and thus further confirm the clinical diagnosis of USH type 2 in this family. In addition, mutations in USH2A have been reported in causing nonsyndromic RP and nonsyndromic deafness [60], further indicating the clinical heterogeneity for USH causative mutations. "
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    ABSTRACT: Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.
    Full-text · Article · May 2014 · PLoS ONE
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    • "c Patient with this change also has two other clearly pathogenic mutations in USH2A. e p.R303H and p.Y1992C were initially described as being pathogenic mutations by Yan et al., 2009 (ref. 29) and McGee et al., 2010 (ref. "
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    ABSTRACT: Usher Syndrome type II (USH2) is an autosomal recessive disorder, characterized by moderate to severe hearing impairment and retinitis pigmentosa (RP). Among the three genes implicated, mutations in the USH2A gene account for 74-90% of the USH2 cases. To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing. Moreover, we performed functional minigene studies for those changes that were predicted to affect splicing. As a result, a total of 144 DNA sequence variants were identified. Based upon previous studies, allele frequencies, segregation analysis, bioinformatics' predictions and in vitro experiments, 37 variants (23 of them novel) were classified as pathogenic mutations. This report provide a wide spectrum of USH2A mutations and clinical features, including atypical Usher syndrome phenotypes resembling Usher syndrome type I. Considering only the patients clearly diagnosed with Usher syndrome type II, and results obtained in this and previous studies, we can state that mutations in USH2A are responsible for 76.1% of USH2 disease in patients of Spanish origin.
    Full-text · Article · Oct 2011 · Orphanet Journal of Rare Diseases
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    • "The p.E3088K missense mutation in USH2A, previously described by Dreyer et al., was present in three out of 306 control alleles, which argues in favor of a non-pathogenic sequence variant [26,28]. The missense mutation p.I5126T in USH2A has been reported as likely pathogenic [87]. We found it in two USH1 patients, who in addition carried two pathogenic mutations in MYO7A. "
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    ABSTRACT: Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.
    Full-text · Article · May 2011 · Orphanet Journal of Rare Diseases
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