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Biochemical, Molecular, and Genetic Mechanisms

Loss-of-Function Mutation in Carotenoid 15,15'-Monooxygenase Identified in a Patient with Hypercarotenemia and Hypovitaminosis A^1–3,

⁴ Departments of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9032; ⁵ Balmoral Surgery, Deal, Kent CT14 7AU, UK; and ⁶ Buckland Hospital, Dover, Kent CT17 0HD, UK

^* To whom correspondence should be addressed. E-mail: stefan.andersson{at}utsouthwestern.edu.

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 (K_m) 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.