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 Tubing en eye hospital with a history of night blindness. In both siblings, plasma retinol binding protein (RBP) concentrations were below the limit of detec tion (<0.6 mu mol/L) and plasma retinol concentrations were extremely low ( 0.19 mu mol/L). interestingly, intestinal absorption of retinyl esters was normal. In addition, other factors associated with low retinol concentratio ns (eg, low plasma transthyretin or zinc concentrations or mutations in the transthyretin gene) were not present. Neither sibling had a history of sys temic disease. Objective: Our aim was to investigate the cause of the retinol deficiency i n 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 R BP gene, and routine laboratory testing. Results: Genomic DNA sequence analysis revealed 2 point mutations in the RE P gene: a T-to-A substitution at nucleotide 1282 of exon 3 and a G-to-A sub stitution at nucleotide 1549 of exon 4. These mutations resulted in amino a cid substitutions of asparagine for isoleucine at position 41 (Ile41-->Asn) and of aspartate for glycine at position 74 (Gly74-->Asp). Sequence analys is of cloned polymerase chain reaction products spanning exons 3 acid 3 sho wed that these mutations were localized on different alleles. The genetic d efect induced severe biochemical vitamin A deficiency but only mild clinica l symptoms (night blindness and a modest retinal dystrophy without effects on growth). Conclusions: We conclude that the cellular supply of vitamin A to target ti ssues might be bypassed in these siblings via circulating retinyl esters, b eta-carotene, or retinoic acid, thereby maintaining the health of periphera l tissues.