A Novel Heterozygous ARL3 Variant in Non-Syndromic Retinitis Pigmentosa: Clinical and Functional Characterization

TL;DR

A new ARL3 gene variant is linked to non-syndromic retinitis pigmentosa, with variable symptoms in family members.

Contribution

Identifies a novel ARL3 variant and demonstrates its role in retinal degeneration with variable expressivity.

Findings

The ARL3 c.199G>C variant disrupts protein expression and ciliogenesis in retinal cells.

Clinical manifestations of the variant show incomplete penetrance and wide intrafamilial variability.

Combining molecular and functional studies aids in diagnosing retinal dystrophies caused by ARL3 mutations.

Abstract

Retinitis pigmentosa (RP) comprises a heterogeneous group of inherited retinal dystrophies characterized by the progressive degeneration of photoreceptors, leading to night blindness and gradual loss of peripheral vision. RP is characterized by a substantial genetic heterogeneity, with more than 85 genes implicated across autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have identified mutations in the ARL3 gene as a causative factor in both syndromic and non-syndromic forms of RP, including autosomal dominant and recessive cases. ARL3 encodes a small GTPase that plays a crucial role in intracellular trafficking, particularly within photoreceptors. This process is critical for maintaining ciliary function and phototransduction. Here, we investigate the pathogenic mechanisms of the ARL3 c.199G>C (p.Asp67His) variant identified in individuals from a four-generation family. We show that mutant ARL3 disrupts normal protein expression and affects ciliogenesis. Clinically affected individuals showed a non-syndromic retinal degenerative RP phenotype, with marked intrafamilial heterogeneity, ranging from extensive retinal atrophy to the absence of clinical manifestation, independent of age. This report highlights the incomplete penetrance and variable expressivity associated with the ARL3 variant and emphasizes the value of combining molecular diagnostics with functional validation to expedite molecular diagnosis.

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