RLBP1 – Retinitis punctata albescens

The RLBP1 gene encodes the cellular retinaldehyde‐binding protein (CRALBP), a key soluble retinoid carrier expressed in the retinal pigment epithelium and Müller cells. Biallelic variants in RLBP1 cause autosomal recessive retinitis punctata albescens, characterized by early‐onset nyctalopia, progressive visual field constriction, and fundus white‐dot deposits. Onset typically occurs in childhood with slow progression to cone‐mediated decline. The disease mechanism involves impaired 11-cis-retinoid trafficking and visual cycle disruption. Genetic testing for RLBP1 variants is essential for accurate diagnosis, family counseling, and eligibility for future gene‐targeted therapies.

Multiple independent studies have identified RLBP1 mutations in ≥19 unrelated probands across at least 12 families (PMID:10102299, PMID:23929416, PMID:28764803). In a seminal SSCP screening of 324 patients, four novel variants were confirmed in three recessive RPA cases (PMID:10102299). A JAMA Ophthalmology series described 11 patients homozygous for a recurrent 7.36-kb deletion of exons 7–9 (PMID:23929416). A Sicilian kindred revealed homozygosity for a frameshift c.398del (p.Pro133GlnfsTer258) allele with segregation in multiple relatives (PMID:28764803). Additional case reports detail compound heterozygous missense mutations (e.g., Gly145Asp/Ile200Thr) and founder effects in Bothnia and Morocco. Segregation analysis has confirmed AR inheritance in 2 affected relatives carrying RLBP1 variants (PMID:14718298).

The variant spectrum comprises at least 28 distinct alleles: 16 missense (e.g., c.700C>T (p.Arg234Trp) (PMID:15953459)) and 8 predicted loss-of-function changes (e.g., c.398del (p.Pro133GlnfsTer258) (PMID:28764803)). Recurrent founder alleles include the Moroccan 7.36-kb exons 7–9 deletion and the Bothnia c.700C>T variant. Splice-site and frameshift mutations further support a haploinsufficiency mechanism. Carrier frequency is low (<0.001 in gnomAD), consistent with a rare AR disorder. Compound heterozygous and homozygous genotypes account for the vast majority of cases, with no dominant phenotypes reported in RPA cohorts.

Functional assays demonstrate that CRALBP mutants disrupt retinoid handling. In vitro studies of R233W and M225K variants show altered ligand binding affinity, impaired 11-cis-retinol carrier function, and reduced rRDH5 activity (PMID:12536144). Zebrafish rlbp1a knockout models recapitulate cone photoreceptor dysfunction, subretinal lipid deposits, and progressive photoreceptor degeneration akin to human RPA (PMID:34668483). Rescue of vision deficits upon wild-type RLBP1 expression further confirms loss-of-function as the pathogenic mechanism. Expression studies localize CRALBP to critical retinal cell types, aligning with human disease pathology.

Some studies highlight locus heterogeneity: screening of 50 Spanish ARRP and 4 RPA families failed to detect RLBP1 mutations, indicating other genetic causes in phenotypically similar cohorts (PMID:11262646). Additionally, fundus white-dot lesions have been observed in RLBP1 heterozygotes without overt RPA, underscoring variable expressivity (PMID:14718298). However, no definitive refuting evidence has emerged, and RLBP1 remains a primary locus for AR RPA.

Integration of genetic and functional data supports a Strong clinical validity rating for RLBP1 in retinitis punctata albescens. Biallelic variants segregate with disease, and biochemical and animal model studies converge on a loss-of-function mechanism disrupting the visual cycle. Although genetic heterogeneity exists, RLBP1 testing yields high diagnostic yield in RPA. Key take-home: RLBP1 mutation screening is clinically useful for confirming AR retinitis punctata albescens, guiding management, and identifying candidates for emerging gene therapies.

References

• Investigative ophthalmology & visual science • 1999 • Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. PMID:10102299
• American journal of ophthalmology • 2004 • A novel compound heterozygous mutation in the cellular retinaldehyde-binding protein gene (RLBP1) in a patient with retinitis punctata albescens. PMID:15234312
• Archives of ophthalmology • 2004 • Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. PMID:14718298
• Ophthalmic genetics • 2001 • Evaluation of RLBP1 in 50 autosomal recessive retinitis pigmentosa and 4 retinitis punctata albescens Spanish families. PMID:11262646
• American journal of ophthalmology • 2005 • Novel mutation in RLBP1 gene in a Japanese patient with retinitis punctata albescens. PMID:15953459
• JAMA ophthalmology • 2013 • Early-onset foveal involvement in retinitis punctata albescens with mutations in RLBP1. PMID:23929416
• Human genomics • 2017 • A novel RLBP1 gene geographical area-related mutation present in a young patient with retinitis punctata albescens. PMID:28764803
• The Journal of biological chemistry • 2003 • Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions. PMID:12536144
• 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

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