RP1L1 – Occult Macular Dystrophy

Occult Macular Dystrophy (OMD) is an autosomal dominant macular disorder characterized by progressive bilateral central vision loss despite a normal fundus appearance, normal fluorescein angiography, and full-field ERG, with pathognomonic loss of the ellipsoid and interdigitation zones on spectral-domain OCT (PMID:20826268). The RP1L1 gene (RP1L1; HGNC:15946) encodes a large photoreceptor-specific protein critical for cone outer segment integrity.

Initial linkage and sequencing studies in four OMD pedigrees identified heterozygous missense variants—p.Arg45Trp and p.Trp960Arg—that segregated with disease in 4 families (PMID:20826268). Subsequent Japanese cohort analysis of 23 patients from 21 families confirmed nine pathogenic RP1L1 missense variants, including recurrent p.Arg45Trp and a cluster between p.Thr1194 and p.Val1201 (PMID:27623337).

An international East Asian study of 36 affected individuals from 21 families reinforced autosomal dominant inheritance, with 60% harboring RP1L1 variants—most frequently p.Arg45Trp (11/21 families) and p.Ser1199Cys (5/21 families)—and demonstrated a correlation between age at onset and visual acuity (PMID:31028767). Parallel Chinese cohort data (15 patients from 9 families) reported p.Arg45Trp in 13 cases and p.Ser1199Cys in 2 cases, with SD-OCT metrics correlating with severity (PMID:32176261).

Functional studies demonstrate retina-specific expression of RP1L1 in cone and rod photoreceptors (PMID:20826268). Patient-derived photoreceptor-like cells carrying p.Arg45Trp exhibit mislocalization of RP1L1 and RP1 proteins, altered PI3K/Akt signaling, and compromised cell viability, supporting a dominant-negative mechanism (PMID:40450528).

Incomplete penetrance and asymptomatic carriers with parafoveal photoreceptor changes have been reported, indicating variable expressivity and the need for multimodal imaging in at-risk relatives (PMID:29196766). However, the preponderance of heterozygous pathogenic RP1L1 missense variants in multiple independent cohorts establishes a definitive AD association.

Key take-home: RP1L1 genetic testing, combined with SD-OCT and mfERG, provides a definitive diagnostic tool for OMD and informs prognosis and genetic counseling.

References

• Am J Hum Genet • 2010 • Dominant mutations in RP1L1 are responsible for occult macular dystrophy. PMID:20826268
• Invest Ophthalmol Vis Sci • 2016 • Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy. PMID:27623337
• Ophthalmology • 2019 • Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease): East Asia Occult Macular Dystrophy Studies Report Number 1. PMID:31028767
• HGG advances • 2025 • Clinical features and molecular mechanisms of RP1L1 variants causing occult macular dystrophy. PMID:40450528

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