MFRP – Retinitis Pigmentosa

MFRP encodes a membrane-type frizzled-related protein expressed in the retinal pigment epithelium (RPE) essential for photoreceptor maintenance. Loss-of-function variants cause an autosomal recessive retinal degeneration syndrome marked by nanophthalmos and rod-cone dystrophy, with early-onset retinitis pigmentosa(PMID:31264930).

Clinical case series detail three consanguineous Spanish siblings and three Portuguese siblings presenting with posterior microphthalmos, retinitis pigmentosa, and foveoschisis carrying homozygous frameshift (c.498del (p.Asn167ThrfsTer25)) and splice-site (c.1124+1G>A) variants segregating in trans(PMID:31264930, PMID:32703043). A separate report of two affected siblings identified compound heterozygous nonsense and missense alleles (p.Cys285Ter; p.Leu412Pro) associated with RP without foveoschisis(PMID:35880649). In total, nine probands across three families and eight additional affected relatives support autosomal recessive inheritance.

The variant spectrum is dominated by truncating alleles: frameshifts (e.g., c.498del (p.Asn167ThrfsTer25)) and canonical splice-donor disruptions (c.1124+1G>A), with less frequent nonsense (p.Cys285Ter) and missense (p.Leu412Pro) substitutions. These variants consistently yield premature termination codons, implicating haploinsufficiency.

Animal studies of the rd6 mouse carrying a splice-donor Mfrp mutation recapitulate progressive photoreceptor loss and RPE abnormalities(PMID:12140190). Adeno-associated viral (AAV)-mediated RPE-targeted Mfrp delivery in rd6 mice preserved outer retinal structure and slowed degeneration, demonstrating functional rescue and confirming pathogenic mechanism via MFRP deficiency(PMID:24664762).

No studies have refuted the MFRP–retinitis pigmentosa link; all reported biallelic truncating or splice variants segregate with disease and produce concordant functional phenotypes in vivo.

Collectively, strong segregation evidence in multiple families and concordant animal model rescue classify the MFRP–retinitis pigmentosa association as Strong. Genetic testing for MFRP truncating variants is warranted in autosomal recessive RP, and gene-replacement therapy offers a viable translational path. Key Take-home: MFRP-related retinitis pigmentosa is a clinically actionable autosomal recessive disorder with proven preclinical rescue strategies.

References

• Ophthalmic genetics • 2019 • Posterior microphthalmos, retinitis pigmentosa, and foveoschisis caused by a mutation in the MFRP gene: a familial study. PMID:31264930
• Ophthalmic genetics • 2020 • A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia. PMID:32703043
• Ophthalmic genetics • 2023 • MFRP variant results in nanophthalmos, retinitis pigmentosa, variability in foveal avascular zone. PMID:35880649
• Human molecular genetics • 2002 • Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. PMID:12140190
• Advances in experimental medicine and biology • 2014 • Gene therapy in the rd6 mouse model of retinal degeneration. PMID:24664762

Evidence Based Scoring (AI generated)