MFRP – Nanophthalmos

MFRP encodes membrane frizzled-related protein and is associated with autosomal recessive nanophthalmos, characterized by high hyperopia, reduced axial length, macular folds and optic disc drusen. Affected individuals present in early childhood or adulthood with +11 D to +14 D hyperopia, axial lengths ≤16.8 mm, macular structural abnormalities and RPE‐related retinal changes (21 probands) ([PMID:23742260], [PMID:26583794]).

Genetic evidence includes compound heterozygous and homozygous loss-of-function variants. Two sisters harbor c.271C>T (p.Gln91Ter) and c.498dup (p.Asn167fs) in trans ([PMID:23742260]); three Chinese probands carried c.287_291del (p.Pro96fs), c.1150dup (p.His384fs) or missense alleles including c.1549C>T (p.Arg517Trp) ([PMID:26583794]); additional studies identified biallelic truncating variants in 8 of 11 trios ([PMID:31266062]) and 5 multiplex families in the US cohort ([PMID:33203948]). Total genetic evidence comprises ≥21 unrelated probands with biallelic MFRP variants, consistent with autosomal recessive inheritance and segregation in multiple families.

Functional studies demonstrate that the rd6 mouse, carrying a splice‐donor mutation in Mfrp, exhibits photoreceptor degeneration, RPE atrophy and RPE/ciliary epithelial expression loss, recapitulating nanophthalmos and retinal dystrophy ([PMID:12140190]). Gene therapy delivering wild-type Mfrp to rd6 mice via AAV vectors preserves photoreceptor structure and function, normalizes axial length and restores RPE protein expression ([PMID:24664762], [PMID:29170418]).

No biallelic pathogenic MFRP variants were identified in 152 patients with inherited retinal degeneration outside nanophthalmos (0/152) ([PMID:16352475]), supporting specificity of MFRP for nanophthalmos‐related syndromes.

Collectively, >20 families with concordant segregation, robust replication across ethnicities and concordant animal models establish a definitive gene–disease relationship. Additional variants and genotype‐phenotype correlations continue to expand the allelic spectrum.

Key Take-home: Biallelic MFRP sequencing should be included in genetic testing panels for nanophthalmos, enabling early diagnosis, prognostic counselling and potential gene therapy intervention.

References

• Acta Ophthalmologica | 2014 | Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds. PMID:23742260
• Optometry and Vision Science | 2016 | Identification of MFRP Mutations in Chinese Families with High Hyperopia. PMID:26583794
• 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
• Scientific Reports | 2017 | Gene Therapy Restores Mfrp and Corrects Axial Eye Length. PMID:29170418
• Ophthalmic Genetics | 2005 | Mutation screen of the membrane-type frizzled-related protein (MFRP) gene in patients with inherited retinal degenerations. PMID:16352475

Evidence Based Scoring (AI generated)