RAX2 – Retinitis Pigmentosa

RAX2 encodes a homeobox-containing transcription factor expressed in retinal progenitor cells. Recent genetic studies have implicated biallelic RAX2 variants in autosomal recessive retinitis pigmentosa (ARRP), expanding its role beyond previously reported dominant cone dystrophies. Establishing this association informs molecular diagnosis and potential therapeutic modeling.

Exome sequencing in a European cohort of 2,086 individuals with inherited retinal disease identified five unrelated index cases harboring biallelic RAX2 variants, all presenting nonsyndromic ARRP with onset ranging from childhood to the mid-40s (average mid-30s) (PMID:30377383). No additional affected relatives were reported in these families, consistent with recessive inheritance.

The variant spectrum includes two missense changes—c.155C>G (p.Pro52Arg) and c.145T>C (p.Ser49Pro)—and a frameshift duplication, c.335dup (p.Ala113fsTer4). Protein structure modeling predicts loss of function for the recessive missense alleles and suggests a founder effect for the recurrent c.335dup variant based on shared haplotypes (PMID:30377383).

Inheritance is autosomal recessive; carrier parents are asymptomatic. Population data indicate these variants are absent or extremely rare in control datasets, supporting pathogenicity of loss-of-function alleles in RAX2.

Functional assessments include in silico modeling demonstrating disruption of the homeobox domain and an induced pluripotent stem cell (iPSC) line generated from a patient carrying c.77C>T (p.Arg26Ter) that was validated for pluripotency and differentiation capacity. This iPSC model provides a platform for studying RAX2-dependent retinogenesis and pathogenesis (PMID:38507880).

Collectively, the convergence of multi-family recessive segregation, a consistent variant spectrum, and complementary functional data supports a Moderate ClinGen-level association between RAX2 and ARRP. RAX2 genetic testing should be considered in unsolved ARRP cases, and patient-derived iPSC lines offer a valuable resource for mechanistic studies and preclinical evaluation.

References

• Genetics in Medicine • 2019 • Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease. PMID:30377383
• Stem Cell Research • 2024 • Generation of an induced pluripotent stem cell line (SJTUGHi001-A) from a patient with Retinitis Pigmentosa carrying c.77C > T mutation in RAX2 gene. PMID:38507880

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