Bitner-Glindzicz, M. et al. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat. Genet. 26, 56-60

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: 29.35). 10/2000; 26(1):56-60. DOI: 10.1038/79178
Source: PubMed


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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Available from: Paul Rutland, Apr 23, 2015
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    • "In these syndromes, the association may have biological implications more than by-chance association. Of note is the Usher-CHI syndrome62,63) in which CHI is associated with the symptoms of Usher syndrome, i.e., hearing loss and retinitis pigmentosa. This association is caused by biallelic deletions encompassing the KATP channel genes at 15p11 and the adjacent USH1C gene at 11p14.3, which is responsible for Usher syndrome. "
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    ABSTRACT: The diagnosis and treatment of congenital hyperinsulinism (CHI) have made a remarkable progress over the past 20 years and, currently, it is relatively rare to see patients who are left with severe psychomotor delay. The improvement was made possible by the recent developments in the understanding of the molecular and pathological basis of CHI. Known etiologies include inactivating mutations of the KATP channel genes (ABCC8 and KCNJ11) and HNF4A, HNF1A, HADH, and UCP2 or activating mutations of GLUD1, GCK, and SLC16A1. The understanding of the focal form of KATP channel CHI and its detection by (18)F-fluoro-L-DOPA positron emission tomography have revolutionized the management of CHI, and many patients can be cured without postoperative diabetes mellitus. The incidence of the focal form appears to be higher in Asian countries; therefore, the establishment of treatment systems is even more important in this population. In addition to diazoxide or long-term subcutaneous infusion of octreotide or glucagon, long-acting octreotide or lanreotide have also been used successfully until spontaneous remission. Because of these medications, near-total pancreatectomy is less often performed even for the diazoxide-unresponsive diffuse form of CHI. Other promising medications include pasireotide, small-molecule correctors such as sulfonylurea or carbamazepine, GLP1 receptor antagonists, or mammalian target of rapamycin inhibitors. Unsolved questions in this field include the identification of the remaining genes responsible for CHI, the mechanisms leading to transient CHI, and the mechanisms responsible for the spontaneous remission of CHI. This article reviews recent developments and hypothesis regarding these questions.
    06/2014; 19(2):57-68. DOI:10.6065/apem.2014.19.2.57
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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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    • "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:// "
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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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