CLRN1 mutations cause nonsyndromic retinitis pigmentosa.

OBJECTIVE: To describe the mutations in the CLRN1 gene in patients from 2 consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP).

DESIGN: Case-series study.

PARTICIPANTS: Affected and unaffected individuals of 2 consanguineous Pakistani families and 90 unaffected controls from the same population. Informed consent was obtained from participants and the protocol was approved by a local institutional review board.

METHODS: Patients of 2 consanguineous families were genotyped with single-nucleotide polymorphism microarrays for genome-wide linkage analysis. The 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's syndrome type III (USH3), which was analyzed by direct sequence analysis. The clinical diagnosis was based on the presence of night blindness, fundoscopic findings, and electroretinography (ERG) results. Additionally, pure tone audiometry was performed to rule out Usher's syndrome.

MAIN OUTCOME MEASURES: Fundoscopy, single-nucleotide polymorphism microarray, DNA sequence analysis, ERG, and audiometry.

RESULTS: Sequencing of CLRN1 revealed novel missense mutations (p.Pro31Leu and p.Leu154Trp) segregating in 2 families. Analysis of fundus photographs indicated attenuation of the retinal vessels, and bone spicule pigmentation in the periphery of the retina. The ERG responses were indicative of a rod-cone pattern of the disease. Audiometric assessment revealed no hearing impairment, thereby excluding Usher's syndrome. Subcellular localization studies demonstrated the retention of the mutant proteins in the endoplasmic reticulum, whereas the wild-type protein was mainly present at the cell membrane.

CONCLUSIONS: The RP-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, because the substituted amino acids located in the transmembrane domains remain polar, whereas more severe changes have been detected in patients with USH3. These data indicate that mutations in CLRN1 are associated not only with USH3, but also with nonsyndromic arRP.