Article

A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene

Department of Clinical and Molecular Genetics, Institute of Child Health, and Great Ormond Street Hospital for Children NHS Trust, London, UK.
Nature Genetics (Impact Factor: 29.65). 10/2000; 26(1):56-60. DOI: 10.1038/79178
Source: PubMed

ABSTRACT Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.

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    • "In addition, a twelfth gene, PDZD7, contributes to USH2 as a modifier of the retinal phenotype on a USH2A background or in digenic inheritance with GPR98 (Ebermann et al. 2010). Multiple isoforms have been described for most of these genes of which, USH1C, PCDH15, USH2A isoforms have been well characterized (Bitner-Glindzicz et al. 2000; Verpy et al. 2000; van Wijk et al. 2004; Ahmed et al. 2008). Mutations in MYO7A, USH1C, CDH23, PCDH15, DFNB31, and CIB2 can also cause nonsyndromic hearing loss (NSHL) and mutations in USH2A and CLRN1 give rise to isolated autosomal recessive RP (see retinal and hearing impairment genetic mutation database, which includes USHbases and other NSHL genes: https:// grenada.lumc.nl/LOVD2/Usher_montpellier/). "
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    ABSTRACT: We show that massively parallel targeted sequencing of 19 genes provides a new and reliable strategy for molecular diagnosis of Usher syndrome (USH) and nonsyndromic deafness, particularly appropriate for these disorders characterized by a high clinical and genetic heterogeneity and a complex structure of several of the genes involved. A series of 71 patients including Usher patients previously screened by Sanger sequencing plus newly referred patients was studied. Ninety-eight percent of the variants previously identified by Sanger sequencing were found by next-generation sequencing (NGS). NGS proved to be efficient as it offers analysis of all relevant genes which is laborious to reach with Sanger sequencing. Among the 13 newly referred Usher patients, both mutations in the same gene were identified in 77% of cases (10 patients) and one candidate pathogenic variant in two additional patients. This work can be considered as pilot for implementing NGS for genetically heterogeneous diseases in clinical service.
    01/2014; 2(1):30-43. DOI:10.1002/mgg3.25
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    • "Exon 1-22 HI Deletion NA Exon 1-22 deletion p.? - (Bitner-Glindzicz, et al., 2000 "
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    • "Type I USH (USH1; MIM] 276900) is characterized by prelingual severe to profound hearing loss, vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa (RP). A total of six USH1 loci have been mapped and mutant alleles underlying USH1B (MIM] 276903), USH1C (MIM] 276904), USHID (MIM] 60167), USHIF (MIM] 602083), and USHIG (MIM] 606943) have been identified in MYO7A (MIM] 276903), USH1C, CDH23, PCDH15, and SANS, respectively [Weil et al., 1995, 2003; Ahmed et al., 2001, 2002; Bitner-Glindzicz et al., 2000; Verpy et al., 2000; Bolz et al., 2001; Bork et al., 2001; Alagramam et al., 2001]. Mutant alleles of CDH23, PCDH15, and USH1C are also associated with recessive nonsyndromic deafness (DFNB) [Verpy et al., 2000; Bork et al., 2001; Astuto et al., 2002b; Ahmed et al., 2002, 2003a, 2003b]. "
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