CLRN1 – Usher syndrome type 3

Clarin-1 is a four-transmembrane protein encoded by CLRN1 that is essential for cochlear hair cell and retinal cell function. Biallelic pathogenic CLRN1 variants cause Usher syndrome type 3, an autosomal recessive disorder characterized by progressive sensorineural hearing impairment, nyctalopia, and rod-cone dystrophy. Genetic testing confirms autosomal recessive inheritance with both homozygous and compound heterozygous variants.

Genetic evidence includes at least 56 unrelated probands: 52 Finnish patients homozygous for a founder p.Tyr100Ter variant (PMID:11524702), 2 Chinese siblings with a novel c.302T>C (p.Val101Asp) transcript variant (PMID:39304915), and multiple Japanese and Canadian families harboring diverse missense and truncating alleles. Segregation analysis across these pedigrees confirms pathogenicity, with affected relatives consistently co-segregating variants. The variant spectrum spans ≥16 missense, ≥10 protein-truncating, several splice-site, and deep intronic alleles, with recurrent founder mutations (p.Tyr100Ter in Finnish and p.Asn48Lys in Ashkenazi Jewish cohorts).

Case series report uniform bilateral sensorineural hearing loss, progressive visual decline, and nyctalopia among variant carriers. Representative variants include c.359T>C (p.Met120Thr) (PMID:11524702) and c.302T>C (p.Val101Asp) (PMID:39304915).

Functional assays demonstrate defective CLRN1 trafficking and stability. In BHK-21 cells, pathogenic variants (p.Asn48Lys, p.Ala123Asp, p.Tyr176Ter) mislocalize to the endoplasmic reticulum, show reduced N-glycosylation, and decreased half-life (PMID:19753315). Clarin-1–mediated actin reorganization is abolished by p.Asn48Lys, implicating cytoskeletal dysregulation in pathogenesis (PMID:19423712).

In vivo, Clrn1-null and Clrn1(N48K) mouse models exhibit disorganized hair bundles, reduced cochlear microphonic potentials, and impaired auditory function (PMID:22787034). Zebrafish clrn1 mutants and transgenics expressing human p.Asn48Lys confirm mislocalization and progressive bundle degeneration, supporting a hypomorphic mechanism and progressive phenotype (PMID:26180195). Antisense oligonucleotides and CRISPR-Cas9 correction of deep intronic splice defects restore normal splicing in cell and mouse retina models (PMID:32841912).

Although most CLRN1 alleles cause USH3, hypomorphic variants (e.g., p.Pro31Leu, p.Leu154Trp) are linked to autosomal recessive non-syndromic retinitis pigmentosa, highlighting allele-specific clinical variability. The strong genetic and functional concordance supports a Strong ClinGen gene-disease validity for CLRN1 with USH3. Key Take-home: CLRN1 testing is clinically actionable in progressive deaf-blind patients and informs prognosis, management, and emerging therapies.

References

• American Journal of Human Genetics • 2001 • Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3 PMID:11524702
• Molecular Vision • 2009 • Disease-causing mutations in the CLRN1 gene alter normal CLRN1 protein trafficking to the plasma membrane. PMID:19753315
• Journal of Biological Chemistry • 2009 • Clarin-1, encoded by the Usher Syndrome III causative gene, forms a membranous microdomain: possible role of clarin-1 in organizing the actin cytoskeleton. PMID:19423712
• The Journal of Neuroscience • 2012 • The mechanosensory structure of the hair cell requires clarin-1, a protein encoded by Usher syndrome III causative gene. PMID:22787034
• The Journal of Neuroscience • 2015 • Zebrafish Models for the Mechanosensory Hair Cell Dysfunction in Usher Syndrome 3 Reveal That Clarin-1 Is an Essential Hair Bundle Protein. PMID:26180195
• Orphanet Journal of Rare Diseases • 2024 • A rare transcript homozygous variants in CLRN1(USH3A) causes Usher syndrome type 3 in a Chinese family. PMID:39304915
• Molecular Therapy: Nucleic Acids • 2020 • Antisense Oligonucleotide- and CRISPR-Cas9-Mediated Rescue of mRNA Splicing for a Deep Intronic CLRN1 Mutation. PMID:32841912

Evidence Based Scoring (AI generated)