CLRN1 – CLRN1-related Retinitis Pigmentosa

Autosomal recessive variants in CLRN1 have been implicated in non-syndromic retinitis pigmentosa (RP) (MONDO:0019200). Patients present with early onset nyctalopia, progressive peripheral vision loss, and characteristic bone-spicule pigmentation. CLRN1-related RP is clinically distinguished from Usher syndrome by absence of hearing impairment and vestibular dysfunction.

Multiple consanguineous families have been reported with biallelic CLRN1 variants segregating with arRP. Two Pakistani families carried missense alleles c.92C>T (p.Pro31Leu) and c.461T>G (p.Leu154Trp), each segregating in homozygous state in affected siblings ([PMID:21310491]). Exome sequencing in four Jordanian families identified two novel CLRN1 variants, including c.323T>C (p.Leu108Pro) and c.433+1G>A, each cosegregating with RP in autosomal recessive fashion ([PMID:31968401]).

An Ashkenazi Jewish patient with non-syndromic RP was found to be compound heterozygous for the common pathogenic missense p.Asn48Lys and a novel deep intronic c.254-643G>T variant, with minigene assays confirming leaky pseudo-exon inclusion ([PMID:39596563]). Collectively, at least five unrelated probands across five pedigrees have confirmed CLRN1 variants with demonstrated segregation.

Functional studies reveal a loss-of-function mechanism. RP-associated missense mutations (p.Pro31Leu, p.Leu154Trp) result in protein retention within the endoplasmic reticulum and reduced stability in BHK-21 cells ([PMID:21310491]). Splice-site and deep intronic variants disrupt normal mRNA processing, as shown by minigene assays, while antisense oligonucleotide and CRISPR-Cas9 approaches rescue correct splicing in retinal cell models ([PMID:32841912]).

Animal and cellular models further support CLRN1’s role in photoreceptor homeostasis. Although zebrafish and mouse models have focused on hair-cell dysfunction, the actin-cytoskeleton organization and membrane trafficking defects observed are consistent with hypomorphic alleles impairing photoreceptor cell architecture.

Together, genetic and experimental data fulfill ClinGen criteria for a Moderate clinical validity classification. CLRN1 should be included in diagnostic gene panels for arRP, with therapeutic potential for splice-modulating interventions.

Key Take-home: Autosomal recessive CLRN1 variants cause hypomorphic loss of function leading to non-syndromic retinitis pigmentosa, with robust genetic segregation and functional rescue supporting moderate clinical validity.

References

• Ophthalmology | 2011 | CLRN1 mutations cause nonsyndromic retinitis pigmentosa. PMID:21310491
• Molecular Genetics & Genomic Medicine | 2020 | Extending the spectrum of CLRN1- and ABCA4-associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing. PMID:31968401
• Genes | 2024 | A Leaky Deep Intronic Splice Variant in CLRN1 Is Associated with Non-Syndromic Retinitis Pigmentosa. PMID:39596563
• Molecular Therapy. Nucleic Acids | 2020 | Antisense Oligonucleotide- and CRISPR-Cas9-Mediated Rescue of mRNA Splicing for a Deep Intronic CLRN1 Mutation. PMID:32841912

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