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Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1 J and nonsyndromic deafness DFNB48

1] Division of Pediatric Otolaryngology/Head & Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [3] Department of Otolaryngology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. [4] Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
Nature Genetics (Impact Factor: 29.65). 09/2012; 44(11). DOI: 10.1038/ng.2426
Source: PubMed

ABSTRACT Sensorineural hearing loss is genetically heterogeneous. Here, we report that mutations in CIB2, which encodes a calcium- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). One mutation in CIB2 is a prevalent cause of deafness DFNB48 in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In mice, CIB2 is localized to the mechanosensory stereocilia of inner ear hair cells and to retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses. Furthermore, in zebrafish and Drosophila melanogaster, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We also show that CIB2 is a new member of the vertebrate Usher interactome.

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Available from: Sulman Basit, Aug 27, 2015
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    • "To date, there are 10 genes known to cause USH (http://hereditaryhearingloss.org). Mutations in 6 genes, MYO7A [5], USH1C [6], CDH23 [7], PCDH15 [8], USH1G [9], and CIB2 [10] have been found causative of USH1. MYO7A is the major gene responsible for USH1 and mutations in MYO7A alone account for 70% of USH1. "
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    ABSTRACT: Background Usher syndrome (USH) is a genetically heterogeneous condition with ten disease-causing genes. The spectrum of genes and mutations causing USH in the Lebanese and Middle Eastern populations has not been described. Consequently, diagnostic approaches designed to screen for previously reported mutations were unlikely to identify the mutations in 11 unrelated families, eight of Lebanese and three of Middle Eastern origins. In addition, six of the ten USH genes consist of more than 20 exons, each, which made mutational analysis by Sanger sequencing of PCR-amplified exons from genomic DNA tedious and costly. The study was aimed at the identification of USH causing genes and mutations in 11 unrelated families with USH type I or II. Methods Whole exome sequencing followed by expanded familial validation by Sanger sequencing. Results We identified disease-causing mutations in all the analyzed patients in four USH genes, MYO7A, USH2A, GPR98 and CDH23. Eleven of the mutations were novel and protein truncating, including a complex rearrangement in GPR98. Conclusion Our data highlight the genetic diversity of Usher syndrome in the Lebanese population and the time and cost-effectiveness of whole exome sequencing approach for mutation analysis of genetically heterogeneous conditions caused by large genes.
    PLoS ONE 09/2014; 9(9). DOI:10.1371/journal.pone.0107326 · 3.23 Impact Factor
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    • "de/gene_sets/219). The recently identified causal Usher genes ABHD12 (Fiskerstrand et al. 2010), CIB2 (Riazuddin et al. 2012), and HARS (Puffenberger et al. 2012) as well as the gene PDZD7 (Ebermann et al. 2010) that is discussed as a modifier in Usher syndrome, could not be included at the time of the bait design and were not part of the NGS analysis. "
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    ABSTRACT: Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next-generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single-nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield.
    09/2014; 2(5). DOI:10.1002/mgg3.92
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    • "USH type 1, accounting for 30% to 40% of total USH, is the most severe clinical form typified by profound congenital deafness, early onset of visual impairment (usually within the first decade of life), and vestibular dysfunction [9]. USH type 1 has been associated with nine genetic loci (USH1B-1H, 1J and 1K), among which six corresponding genes were identified including MYO7A (USH1B) [8], USH1C (USH1C) [10], CDH23 (USH1D) [11], PCDH15 (USH1F) [12], USH1G (USH1G) [13], and CIB2 (USH1J) [14]. USH type 2, the most common form of USH, is presented with much less severer phenotypes than USH type 1 [9]. "
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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.
    PLoS ONE 05/2014; 9(5):e97808. DOI:10.1371/journal.pone.0097808 · 3.23 Impact Factor
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