title: Loss-of-function mutation in carotenoid 15,15'-monooxygenase identified in a patient with hypercarotenemia and hypovitaminosis A.
abstract: 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.
authors.affiliation: Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9032, USA.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindqvist
authors.forename: John
authors.initials: J
authors.lastname: Sharvill
authors.forename: Denis E
authors.initials: DE
authors.lastname: Sharvill
authors.forename: Stefan
authors.initials: S
authors.lastname: Andersson
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002338:Carotenoids / Q000097:blood* / Q000378:metabolism; D018929:Cell Culture Techniques; D002850:Chromatography, Gel; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005091:Exons; D006580:Genetic Carrier Screening; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014802:Vitamin A Deficiency / Q000201:enzymology / Q000235:genetics*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000172:deficiency / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D017931:DNA Primers; D011994:Recombinant Proteins; D002338:Carotenoids; D004247:DNA; C493358:BCO1 protein, human; D050559:beta-Carotene 15,15'-Monooxygenase