PROM1 – Retinitis Pigmentosa

Prominin-1 (PROM1) is a pentaspan transmembrane glycoprotein localized to photoreceptor disc membranes. Bi-allelic loss-of-function variants in PROM1 underlie autosomal recessive retinitis pigmentosa ([MONDO:0019200]). Pathogenic PROM1 variants disrupt outer segment homeostasis, leading to progressive rod-cone degeneration and characteristic bone-spicule pigmentation.

Genetically, PROM1-related RP follows an autosomal recessive inheritance pattern. Two unrelated sporadic RP patients were found to harbor a homozygous frameshift variant, c.1445dupT (p.Phe482fs), in exon 12, with complete co-segregation in their families and absence in 200 controls (2 probands) ([PMID:27082927]). A large consanguineous Spanish pedigree exhibited a homozygous c.869delG (p.Ser290fs) variant causing premature truncation, nonsense-mediated decay, and absence of PROM1 protein in patient lymphocytes, cosegregating with RP in ≥3 affected relatives ([PMID:20042663]).

The variant spectrum in RP includes frameshift and splice-site changes: one non-canonical intronic splice alterant, c.221-20T>G, was identified by whole-genome sequencing in unsolved IRD cases and shown to disrupt PROM1 splicing ([PMID:38816995]). Deep intronic mutations and canonical splice variants further support a loss-of-function mechanism across diverse populations.

Functional studies corroborate pathogenicity. Patient cells with c.869delG exhibit aberrant transcripts degraded by NMD, consistent with haploinsufficiency ([PMID:20042663]). Prom1−/− mice develop photoreceptor degeneration in a light-dependent manner reversed by dark rearing, with retinal thinning and functional deficits mirroring human RP ([PMID:25414197]). RPE assays demonstrate that Prom1 loss impairs autophagy flux via mTOR dysregulation and p62 accumulation, linking cellular homeostasis to photoreceptor survival ([PMID:28437526]).

Some heterozygous missense variants (e.g., c.1117C>T (p.Arg373Cys)) produce autosomal dominant macular dystrophy with peripheral bone-spicule changes, occasionally misclassified as RP, reflecting allelic and stage-dependent phenotypic spectra ([PMID:20393116]; [PMID:34008001]). However, AR truncating and splicing alleles consistently result in classic RP.

Collectively, the genetic and experimental concordance supports a Moderate clinical validity for PROM1 in autosomal recessive RP, with robust segregation and functional concordance. PROM1 variant screening should be included in RP diagnostic panels to inform early genetic counseling and guide future gene-targeted therapies.

References

• International journal of molecular medicine • 2016 • Whole-exome sequencing identifies a novel homozygous frameshift mutation in the PROM1 gene as a causative mutation in two patients with sporadic retinitis pigmentosa. [PMID:27082927]
• 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]
• Investigative ophthalmology & visual science • 2017 • Prominin-1 Is a Novel Regulator of Autophagy in the Human Retinal Pigment Epithelium. [PMID:28437526]
• American journal of ophthalmology • 2019 • Expanded Phenotypic Spectrum of Retinopathies Associated with Autosomal Recessive and Dominant Mutations in PROM1. [PMID:31129250]
• HGG advances • 2024 • Whole genome sequencing identifies elusive variants in genetically unsolved Italian inherited retinal disease patients. [PMID:38816995]
  

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