Loss-of-Function Mutation in Carotenoid 15,15'-Monooxygenase Identified in a Patient with Hypercarotenemia and Hypovitaminosis A

• Published in: The Journal of nutrition Vol. 137; no. 11; pp. 2346 - 2350
• Main Authors: Lindqvist, Annika, Sharvill, John, Sharvill, Denis E, Andersson, Stefan
• Format: Journal Article
• Language: English
• Published: United States American Society for Nutrition 01.11.2007
• Subjects: Amino Acid Sequence; amino acid sequences; Base Sequence; beta-Carotene 15,15'-Monooxygenase; beta-Carotene 15,15'-Monooxygenase - deficiency; beta-Carotene 15,15'-Monooxygenase - genetics; beta-Carotene 15,15'-Monooxygenase - isolation & purification; blood; carotenoid 15,15'-monooxygenase; Carotenoids; Carotenoids - blood; Carotenoids - metabolism; case studies; Cell Culture Techniques; Chromatography, Gel; deficiency; DNA; DNA - genetics; DNA - isolation & purification; DNA Primers; enzyme activity; enzymology; Exons; genes; Genetic Carrier Screening; Genetic Vectors; genetics; Humans; hypercarotenemia; hypovitaminosis A1-3; isolation & purification; metabolism; methionine; missense mutation; Molecular Sequence Data; Mutation; patients; Plasmids; Polymerase Chain Reaction; Recombinant Proteins; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; single nucleotide polymorphism; threonine; vitamin A; Vitamin A Deficiency; Vitamin A Deficiency - enzymology; Vitamin A Deficiency - genetics
• ISSN: 0022-3166; 1541-6100
• DOI: 10.1093/jn/137.11.2346

The enzyme carotenoid 15,15'-monooxygenase (CMO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A in the small intestine. Plant carotenoids are an important dietary source of vitamin A (retinol) and the sole source of vitamin A for vegetarians. Vitamin A is essential for normal embryonic development as well as normal physiological functions in children and adults. Here, we describe one heterozygous T170M missense mutation in the CMO1 gene in a subject with hypercarotenemia and mild hypovitaminosis A. The replacement of a highly conserved threonine with methionine results in a 90% reduction in enzyme activity when analyzed in vitro using purified recombinant enzymes. The Michaelis-Menten constant (Km) for the mutated enzyme is normal. Ample amounts of carotenoids are present in plasma of persons consuming a normal Western diet, suggesting that the enzyme is saturated with substrate under normal conditions. Therefore, we propose that haploinsufficiency of the CMO1 enzyme may cause symptoms of hypercarotenemia and hypovitaminosis A in individuals consuming a carotenoid-containing and vitamin A-deficient diet.