Biochemical but not clinical, vitamin A deficiency results from mutations in the gene for retinol binding protein

Background: Two German sisters aged 14 and 17 y were admitted to the Tubingen eye hospital with a history of night blindness. In both siblings, plasma retinol binding protein (RBP) concentrations were below the limit of detection (<0.6 μmol/L) and plasma retinol concentrations were extremely low (0.19 μmol/L). Interestingly, intestinal absorption of retinyl esters was normal. In addition, other factors associated with low retinol concentrations (eg, low plasma transthyretin or zinc concentrations or mutations in the transthyretin gene) were not present. Neither sibling had a history of systemic disease. Objective: Our aim was to investigate the cause of the retinol deficiency in these 2 siblings. Design: The 2 siblings and their mother were examined clinically, including administration of the relative- dose-response test, DNA sequencing of the RBP gene, and routine laboratory testing. Results: Genomic DNA sequence analysis revealed 2 point mutations in the RBP gene: a T-to-A substitution at nucleotide 1282 of exon 3 and a G-to- A substitution at nucleotide 1549 of exon 4. These mutations resulted in amino acid substitutions of asparagine for isoleucine at position 41 (Ile41→Asn) and of aspartate for glycine at position 74 (Gly74→Asp). Sequence analysis of cloned polymerase chain reaction products spanning exons 3 and 4 showed that these mutations were localized on different alleles. The genetic defect induced severe biochemical vitamin A deficiency but only mild clinical symptoms (night blindness and a modest retinal dystrophy without effects on growth). Conclusions: We conclude that the cellular supply of vitamin A to target tissues might be bypassed in these siblings via circulating retinyl esters, β-carotene, or retinoic acid, thereby maintaining the health of peripheral tissues.