RLBP1 – Newfoundland Cone-Rod Dystrophy

Newfoundland cone-rod dystrophy (NFRCD) is an early-onset autosomal recessive retinal dystrophy characterized by night blindness, rapid photoreceptor degeneration, and early visual field constriction. In a geographic isolate of Newfoundland, genome-wide linkage localized NFRCD to chromosome 15q encompassing RLBP1, and biallelic splice-site variants c.141+1G>C and c.141+2T>C were identified in affected members of two unrelated pedigrees, each variant segregating with disease and predicted to abolish normal mRNA splicing (PMID:11868161).

A subsequent clinical series of RLBP1-related retinopathies highlighted a spectrum ranging from fundus albipunctatus to mild NFRCD, underscoring that complete loss-of-function alleles produce the most severe, early-onset cone–rod phenotype (PMID:25429852).

The RLBP1 variant spectrum for NFRCD is dominated by null alleles: the canonical intron 2 splice-donor mutation c.141+1G>C (p.?) and its neighbour c.141+2T>C (p.?) both lead to premature truncation and loss of CRALBP function (PMID:11868161).

Functional modeling in zebrafish demonstrates that rlbp1a knockout larvae exhibit attenuated cone photoreceptor responses, accumulation of subretinal retinyl esters, cone and rod dystrophy, and retinal thinning, faithfully recapitulating human NFRCD pathology (PMID:34668483).

Biochemical assays of recombinant CRALBP further reveal that the p.Met226Lys (formerly M225K) mutation abolishes retinoid binding and substrate carrier activity in vitro, supporting a loss-of-function mechanism for severe RLBP1-associated dystrophies (PMID:12536144).

Together, these data establish that biallelic loss-of-function mutations in RLBP1 cause Newfoundland cone-rod dystrophy (Newfoundland cone-rod dystrophy). Genetic testing for splice-site and other null variants in RLBP1 should be considered in patients with early-onset cone–rod dystrophy. Key take-home: CRALBP loss-of-function underlies severe NFRCD and is amenable to genetic diagnosis.

References

• American journal of human genetics • 2002 • Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. PMID:11868161
• eLife • 2021 • Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina. PMID:34668483
• The Journal of biological chemistry • 2003 • Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions. PMID:12536144

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