ROM1 – Retinitis Pigmentosa

ROM1 encodes rod outer segment membrane protein 1 and is implicated in digenic retinitis pigmentosa (RP) in combination with peripherin/RDS (PRPH2). In three families, individuals heterozygous for ROM1 frameshift variants c.339dup (p.Leu114fs) and c.239dup (p.Val81fs) and concurrent PRPH2 mutations developed RP, whereas single heterozygotes were unaffected (PMID:8202715). A subsequent series of four unrelated index patients carried heterozygous ROM1 missense variant c.793G>A (p.Ala265Thr) together with PRPH2 c.554T>C (p.Leu185Pro) and manifested RP, confirming the two-locus digenic inheritance; no cases of ROM1 monogenic RP have been reported (PMID:9331261).

Functional modeling in transgenic and knockout mice demonstrated that simultaneous reduction of Rom1 and Rds/peripherin to below ~60% of wild-type levels accelerates photoreceptor degeneration, with histological, electroretinographic and biochemical defects recapitulating the human digenic phenotype (PMID:11427722). These data support a haploinsufficiency mechanism requiring combined deficiency of ROM1 and PRPH2.

Key Take-home: ROM1 variants alone do not cause RP but serve as essential digenic partners with PRPH2; screening for ROM1 should be considered in RP patients with known PRPH2 mutations.

References

• Science • 1994 • Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. PMID:8202715
• Investigative ophthalmology & visual science • 1997 • Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. PMID:9331261
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa. PMID:11427722

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