PROM1 – Cone-Rod Dystrophy

The association of the transmembrane glycoprotein PROM1 with Cone-Rod Dystrophy was first uncovered by genome-wide homozygosity mapping in eight families, including nonconsanguineous pedigrees, identifying PROM1 variants in one family with autosomal recessive cone-rod dystrophy (PMID:20554613). Subsequent whole-genome sequencing in a consanguineous family revealed a deep intronic variant in PROM1, c.2077-521A>G, causing pseudoexon activation and a premature termination codon, consistent with a null allele mechanism (PMID:26153215).

Genetic evidence supports an autosomal recessive mode of inheritance, with segregation of homozygous and compound heterozygous variants in multiple affected siblings and families. Key disease-causing alleles include frameshift variants (e.g., c.1612del (p.Trp538GlyfsTer15)), canonical splice-site mutations, and deep intronic changes leading to aberrant splicing (PMID:29769798). Segregation in at least three consanguineous families and variant co-segregation in multiple nonconsanguineous kindreds underscore the reproducibility of the genetic findings.

Functional studies corroborate a loss-of-function mechanism. Minigene splicing assays confirm pseudoexon inclusion for c.2077-521A>G, leading to premature termination (PMID:26153215). Prom1 knockout mouse models develop early photoreceptor degeneration that is light-dependent and linked to disrupted outer segment morphogenesis; dark rearing and fenretinide treatment modulate degeneration, demonstrating phenotype rescue potential (PMID:25414197). In human retinal pigment epithelium, Prom1 regulates autophagy via mTOR suppression and interactions with p62/HDAC6, supporting its role in photoreceptor maintenance (PMID:28437526).

No credible conflicting evidence disputing the PROM1–cone-rod dystrophy relationship has been reported to date. Collectively, the genetic and functional data provide a definitive link between PROM1 loss-of-function and autosomal recessive cone-rod dystrophy. PROM1 variant screening should be integrated into diagnostic panels for cone-rod dystrophy, and future therapies may target splicing or supplement PROM1 function.

Key take-home: PROM1 loss-of-function variants cause autosomal recessive cone-rod dystrophy through defective photoreceptor outer segment biogenesis and impaired autophagy, making PROM1 a critical diagnostic and therapeutic target in cone-rod dystrophy.

References

• Investigative Ophthalmology & Visual Science • 2010 • Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations. PMID:20554613
• European Journal of Human Genetics • 2016 • Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation. PMID:26153215
• Molecular Vision • 2018 • Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy. PMID:29769798
• 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
• JAMA Network Open • 2019 • Clinical and Molecular Characterization of PROM1-Related Retinal Degeneration. PMID:31199449

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