PROM1 – inherited retinal dystrophy

The association between PROM1 and inherited retinal dystrophy is supported by strong genetic and experimental evidence. Heterozygous missense variant c.1117C>T (p.Arg373Cys) segregates with disease in seven patients from five unrelated families (PMID:38072963). In five Caribbean, British, and Italian pedigrees, p.Arg373Cys cosegregated in 41 affected individuals exhibiting bull’s-eye maculopathy and rod-cone dysfunction (PMID:20393116). A homozygous frameshift variant c.869del (p.Ser290Ter) was identified in a large consanguineous Spanish family with autosomal recessive retinitis pigmentosa, with full segregation and evidence of nonsense-mediated decay (PMID:20042663).

Genetic evidence spans autosomal dominant (AD) and autosomal recessive (AR) inheritance. In AD cases, p.Arg373Cys recurred across ethnicities with complete penetrance and interfamilial variability. AR cases include truncating and splice-site mutations causing null alleles. Overall, more than 15 distinct pathogenic variants in over 50 families have been reported, meeting the ClinGen genetic evidence cap (PMID:38072963, PMID:20042663).

Clinically, PROM1-related retinal dystrophy manifests primarily as macular degeneration with variable peripheral retinal involvement (HP:0007769). Patients show early central vision loss, concentric macular atrophy, and in many cases peripheral bone-spicule pigmentation on fundus examination (PMID:38072963, PMID:20393116). Electroretinography often reveals cone-rod dysfunction, correlating with genotype and inheritance mode.

Functional studies demonstrate a loss-of-function mechanism. Prom1 knockout mice exhibit malformed outer segments, early photoreceptor dysfunction, and RPE degeneration (PMID:25414197, PMID:39513868). In human RPE cells, Prom1 regulates autophagy via mTOR suppression and p62 interaction; knockdown impairs cellular homeostasis (PMID:28437526).

Whole-genome sequencing in unsolved IRD cases identified a non-canonical splice variant in PROM1, confirming the impact of non-coding mutations on splicing and disease (PMID:38816995). No conflicting genetic linkage has been reported, and variant pathogenicity is consistently supported across studies.

In summary, PROM1 demonstrates a strong gene-disease association with inherited retinal dystrophy via both AD and AR loss-of-function variants. This supports its inclusion in diagnostic gene panels and informs genotype-specific counseling and potential gene therapy strategies.

References

• Scientific reports • 2023 • Genetic and clinical characteristics of PROM1-related retinal degeneration in Korean. PMID:38072963
• Investigative ophthalmology & visual science • 2010 • The PROM1 mutation p.R373C causes an autosomal dominant bull's eye maculopathy associated with rod, rod-cone, and macular dystrophy. PMID:20393116
• Investigative ophthalmology & visual science • 2010 • Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1. PMID:20042663
• Investigative ophthalmology & visual science • 2014 • Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice. PMID:25414197
• Cells • 2024 • Prominin-1 Knockdown Causes RPE Degeneration in a Mouse Model. PMID:39513868
• HGG advances • 2024 • Whole genome sequencing identifies elusive variants in genetically unsolved Italian inherited retinal disease patients. PMID:38816995

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