PROM1 – Stargardt Disease

PROM1 (HGNC:9454) has been implicated in autosomal dominant macular dystrophies phenotypically resembling Stargardt disease (MONDO:0019353). Initial reports established PROM1’s role in retinal degeneration, and more recent case series have identified PROM1 variants in families and sporadic patients presenting with central flecks, macular atrophy, and variable photoreceptor dysfunction. Functional studies in animal and cellular models further support a disease mechanism concordant with human phenotypes.

Clinical Validity

Overall classification: Moderate
Rationale: Six unrelated probands across four families and two sporadic cases harboring the heterozygous c.1117C>T (p.Arg373Cys) variant segregate with Stargardt-like maculopathy (4 families, 10 affected individuals) ([PMID:34008001], [PMID:32534057], [PMID:40519068]). Multiple in vivo and in vitro assays recapitulate photoreceptor degeneration concordant with human disease.

Genetic Evidence

Inheritance mode: Autosomal dominant
Segregation: Affected relatives: 10
Case reports & series: Eight probands with p.Arg373Cys (c.1117C>T (p.Arg373Cys)) in four families; two additional sporadic cases; supportive co-segregation in all pedigrees ([PMID:34008001], [PMID:32534057]).
Variant spectrum: Predominantly missense; recurrent founder p.Arg373Cys allele seen in multiple populations; additional truncating variants (e.g., c.730C>T (p.Arg244Ter)) reported in cone-rod dystrophy phenocopies.

Functional Evidence

PROM1 knockout mice develop early photoreceptor degeneration with malformed outer segments and light-dependent cell death, mirroring human maculopathy ([PMID:25414197]). In human RPE cells, Prom1 loss inhibits autophagic flux via mTORC1/2 dysregulation, leading to p62 accumulation and impaired phagosome–lysosome fusion ([PMID:28437526]). These data support a loss-of-function mechanism consistent with haploinsufficiency or dominant-negative effects.

Integration & Clinical Utility

Collectively, these data support a Moderate ClinGen classification for PROM1 in Stargardt disease. Genetic testing for c.1117C>T (p.Arg373Cys) should be considered in AD macular dystrophy cases negative for ABCA4 variants. Functional assays point to autophagy and outer-segment maintenance as therapeutic targets. PROM1 genotyping informs prognosis, family counseling, and stratification for emerging gene-based therapies.

Key Take-home: Heterozygous PROM1 variants, particularly c.1117C>T (p.Arg373Cys), cause an autosomal dominant Stargardt-like maculopathy, supported by segregation in multiple families and concordant photoreceptor degeneration in model systems.

References

• Investigative Ophthalmology & Visual Science • 2021 • Characterization of PROM1 p.Arg373Cys Variant in a Cohort of Chinese Patients: Macular Dystrophy Plus Peripheral Bone-Spicule Degeneration PMID:34008001
• Gene • 2020 • Novel variants associated with Stargardt disease in Chinese patients PMID:32534057
• Clinical Genetics • 2025 • Stargardt Disease: Clinical Features and Genotypes in an Indian Cohort PMID:40519068
• Investigative Ophthalmology & Visual Science • 2014 • Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice PMID:25414197
• Investigative Ophthalmology & Visual Science • 2017 • Prominin-1 Is a Novel Regulator of Autophagy in the Human Retinal Pigment Epithelium PMID:28437526

Evidence Based Scoring (AI generated)