Clarin 1, encoded by the CLRN1 gene, is a protein consisting of multiple helical transmembrane domains, a cytosolic N-terminal and a C-terminal endoplasmic-reticulum membrane retention signal (TKGH). While the exact molecular function of clarin 1 is yet to be fully characterized, it is believed to play a role in actin filament organization, auditory receptor cell stereocilium organization, equilibrioception, photoreceptor cell maintenance and cell motility.
The gene has been implicated in Usher Syndrome, type IIIA (USH3A), a disorder characterized by a combination of progressive sensorineural hearing loss and decreasing visual acuity. It has also been associated with non-syndromic Retinitis Pigmentosa 61, an ocular disorder of progressive retinal degeneration resulting in the gradual loss of peripheral vision.
The gene is located on the long arm of chromosome 3. It spans a length of 54 kb of DNA and its coding sequence is spread across 7 exons. The gene encodes a 25.7 kDa protein product made up of 232 amino acids. Several isoforms of the CLRN1 gene exist due to alternatively spliced transcript variants. The gene is found to be ubiquitously expressed in the human body. Only 30 supposedly pathogenic variants of the CLRN1 gene have been annotated in the Human Gene Mutation Database. These include missense mutations, insertions and deletions.
Khan et al. (2017) studied a consanguineous Saudi family with four siblings affected by Usher syndrome. When an NGS panel of Usher genes and WES failed to identify mutations, a genome-wide linkage analysis and Whole Genome Sequencing (WGS) method was employed. This helped identify a homozygous deep intronic mutation, c.254–649T>G in the CLRN1 gene associated with USH3A. The mutation was predicted to generate a novel donor splice site and a CLRN1 minigene splice assay was carried out to study its effects. The mutation was shown to result in the splicing of an aberrant exon, resulting in a frameshift and a premature termination codon. This is the first reported case of a CLRN1 associated Usher diagnosis in Saudi Arabia. The authors also screened an additional 7 Saudi Usher patients and found the CLRN1 mutation in two of them. Microsatellite marker analysis indicated c.254–649T>G to represent a founder allele in the Saudi population. The authors stressed the benefit of using WGS to identify intronic hidden mutations in patients that do not carry exonic mutations.
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