The RLBP1 gene is located on 15q26.1 chromosome, it encodes a 36-kD water-soluble protein that comprises a 317 amino acids. It carries 11-cis-retinaldehyde or 11-cis-retinal as physiologic ligands, which is a component of the visual cycle. It plays a role in the regeneration of active 11-cis-retinol and 11-cis-retinaldehyde, from the inactive 11-trans products of the rhodopsin photocycle and in the de novo synthesis of these retinoids from 11-trans metabolic precursors. Defects in this protein are the cause of retinitis punctata albescens, a rare hereditary chorioretinal dystrophy characterized by a delay in the regeneration of cone and rod photopigments.
he RLBP1 gene consists of seven coding exons and spans approximately 12 kb in the genomic DNA. Mutations in the RLBP1, PRPH2, and RDH5 genes have been associated with fundus albipunctatus disease. Mutations in PRPH2 is consistent with the autosomal dominant pattern of inheritance, while mutations in RDH5 result in an autosomal recessive pattern.
Humbert et al. (2006) studied a 24-year-old Moroccan patient with typical fundus albipunctatus, born of first-cousin parents. He carried a 7.36-kb homozygous deletion encompassing the last 3 exons of RLBP1 (7, 8, and 9) and part of the intergenic region between RLBP1 and ABHD2, which lies downstream of RLBP1. This deletion abolished the retinal binding site of CRALBP. The telomeric breakpoint of the deletion (in RLBP1 intron 6) is embedded in an Alu element, whereas the centromeric breakpoint (in the intergenic region) lies between two Alu elements placed in the opposite orientation.
Dessalces et al. (2013) performed clinical and molecular investigations in patients with retinitis punctata albescens (RPA) at various ages, from November 2003, through June 2012, with no planned patient follow-up. The study included 11 patients with RPA (mean age, 24 [range, 3-39] years) from seven families and 11 control subjects undergoing evaluation. All patients had night blindness (before age 6 years in 10). Screening for mutations in the RLBP1 gene uncovered two novel mutations (p.Tyr111X and p.Arg9Cys). Eight patients from Morocco were homozygous for the recurrent 7.36-kilobase RLBP1 deletion of exons 7 through 9.
Katsanis et al. (2001) performed direct sequencing for the RLBP1 and RDH5 genes in four consanguineous Saudi families affected with retinitis punctata albescens. A homozygous p.R150Q missense mutation was identified in the RLBP1 gene in one of the families, affecting a highly conserved residue in the protein and probably resulting in a slowly progressive disease. Other genes were tested for the affected patients including: RHO, RDS, ABCR, TIMP3 and EFEMP1. None of these genes were associated with the disease in the three Saudi families.
Monies et al. (2017) analyzed the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 16-year-old male, suffered from seizures, retinitis pigmentosa and obesity. His parents were consanguineous and he had a family history of this phenotype. Whole exome sequencing helped identify a dual molecular diagnosis in this patient. A homozygous mutation (c.773T>G, p.L258W) was found in exon 8 of the patient’s RLBP1 gene, associated with Bothnia retinal dystrophy. The patient also had a heterozygous variant (c.1471C>T, p.R491X) in exon 7 of the SYT9 gene and this was suggested to be associated with epilepsy. The authors noted that dual molecular diagnoses were rare and only occurred in 1.5% of the cohort.
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