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Muhammad I. Khan, Ferry F. Kersten, Maleeha Azam, Rob W. Collin, Alamdar Hussain, Hannie Kremer, Frans P. Cremers, Raheel Qamar, Anneke I. den Hollander; CLRN1 Mutations Cause Non-Syndromic Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5405.
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To identify the genetic cause in patients from two consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP).
Patients of two consanguineous families were genotyped with single nucleotide polymorphism (SNP) microarrays for genome-wide linkage analysis. A search for potential candidate genes within the 8-Mb overlapping homozygous region in these families revealed the presence of CLRN1, a gene previously known to cause Usher syndrome type III (USH3), which was analysed by direct sequence analysis. The clinical diagnosis was based on the presence of night blindness, fundoscopy and electroretinography (ERG). In addition, pure tone audiometry was performed to rule out Usher syndrome.
Sequencing of CLRN1 revealed novel missense mutations (c.92C>T [p.Pro31Leu] and c.461T>G [p.Leu154Trp]) segregating in the two families. Analysis of fundus photographs indicated attenuation of the retinal vessels, and bone spicule pigmentation in the periphery of the retina. ERG responses were indicative of a rod-cone pattern of the disease. Audiometric assessment revealed no hearing impairment, thereby excluding Usher syndrome. Subcellular localization studies in hTERT-RPE1 cells demonstrated that mutant clarin-1 proteins were retained in the endoplasmic reticulum, whereas wild type clarin-1 was mainly present at the cell membrane.
The RP-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, as the substituted amino acids that are located in the transmembrane domains remain polar, while more severe changes have been detected in patients with USH3. Our data indicate that mutations in CLRN1 are associated not only with Usher syndrome type III, but also with non-syndromic arRP.
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