RLBP1 – Retinitis pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous retinal dystrophy characterized by progressive photoreceptor degeneration, night blindness, and peripheral visual field constriction. RLBP1 encodes the cellular retinaldehyde-binding protein (CRALBP), a soluble retinoid carrier in the visual cycle. Autosomal recessive mutations in RLBP1 underlie several RP phenotypes, including Bothnia dystrophy and fundus albipunctatus, establishing its role in RP pathogenesis.

Bi-allelic RLBP1 variants have been identified in seven patients from five unrelated families and ten additional compound heterozygous individuals, with recurrent founder alleles c.677T>A (p.Met226Lys) and c.700C>T (p.Arg234Trp) prevalent in northern Sweden ([PMID:25429852]; [PMID:18344446]). Early gene‐mapping studies first listed RLBP1 among autosomal recessive RP genes ([PMID:11559856]).

Inheritance is autosomal recessive, with segregation confirmed in all affected pedigrees ([PMID:18344446]). The variant spectrum includes multiple truncating changes (e.g., c.811del (p.Asp271fs)), canonical splice‐site variants (c.141+1G>C), and missense substitutions such as c.700C>T (p.Arg234Trp).

Functional assays demonstrate that the M225K mutation (c.677T>A) abolishes CRALBP retinoid binding and substrate carrier activity, while the R233W change tightens ligand affinity but still impairs enzymatic interactions ([PMID:12536144]). A zebrafish rlbp1a knockout recapitulates human RP phenotypes, showing reduced chromophore levels, cone dysfunction, subretinal lipid deposition, and photoreceptor degeneration consistent with CRALBP loss-of-function ([PMID:34668483]).

No robust conflicting data have been reported disputing the RLBP1–RP association. Genetic, biochemical, and animal model evidence are concordant and reproducible across populations.

RLBP1 meets Strong ClinGen criteria for autosomal recessive RP, with robust segregation, a broad spectrum of pathogenic variants, and functional validation in vitro and in vivo. RLBP1 variant screening is recommended for molecular diagnosis, carrier testing, and patient stratification in clinical and research settings.

Key take-home: Biallelic RLBP1 variants cause autosomal recessive retinitis pigmentosa through a loss-of-function mechanism, informing diagnostic and therapeutic strategies.

References

• Ophthalmic genetics | 2001 | Update on the molecular genetics of retinitis pigmentosa. [PMID:11559856]
• Investigative ophthalmology & visual science | 2008 | Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1. [PMID:18344446]
• 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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