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

Abstract

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa1. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E (refs 26). 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 hyperinsulinism7,8,9,10. 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 (ref. 11). 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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Figure 1: Two extended families with multiple affected members.
Figure 2: Schematic representation of the critical regions for Usher 1C and DFNB18.
Figure 3: Multiplex PCR assay.
Figure 4: Immunohistochemistry using anti-USH1C monoclonal antibody.
Figure 5: Sequencing of exon 3 in family 3.
Figure 6: Analysis of Acadian cell lines.

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Acknowledgements

We thank the patients and their families for participation; their treating physicians, especially K. Rajput and W. van't Hoff, for assistance; S. Bundey for help establishing the Usher clinic; R. James and S. Swift for providing the β-cell preparations for in vitro study; D. Rampling for help with immuno-staining; R. Mueller for providing DNA from Pakistani controls; A. Kriss for electroretinograms; J. Liang and L. Michaels for help with interpretation of immunostaining; G. Evans and M. Athanasiou for PAC clones for FISH studies; and Defeating Deafness for pump priming this research. M.B.-G. is funded by an M.R.C. Clinician Scientist Fellowship. This work was under-taken in part by Great Ormond Street Hospital for Children NHS Trust, which received a proportion of its funding from the NHS Executive. We acknowledge the Medical Research Council (UK) and ‘Jeans for Genes’ for funding the Transgenomic WAVE Fragment Analysis System (DHPLC), and the Wellcome Trust for the ABI sequencer. B.G. was supported in part by grant 4201 from the Israel Ministry of Health and a grant from the Israel Science Foundation founded by the Academy of Sciences and Humanities. M.J.D. was supported by the British Diabetic Association and the Medical Research Council (UK). Grant BMH4-CT98-3284, awarded as part of the European Commission Biomed 2 program, provided support for international collaborations. X.L. was supported by the Deafness Research Foundation and Grant DC04530.

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Correspondence to Maria Bitner-Glindzicz or Benjamin Glaser.

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Bitner-Glindzicz, M., Lindley, K., Rutland, P. et al. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet 26, 56–60 (2000). https://doi.org/10.1038/79178

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