Loss-of-function mutation in carotenoid 15,15′-monooxygenase identified in a patient with hypercarotenemia and hypovitaminosis A

Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9032, USA.
Journal of Nutrition (Impact Factor: 3.88). 12/2007; 137(11):2346-50.
Source: PubMed


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.

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    • "It was proven that a mutation in carotenoid 15, 15´monooxygenase (CMO1) which catalyses the first step in the conversion of dietary pro-vitamin A carotenoids to vitamin A in the small intestine cause symptoms of hypercarotenaemia (Lindqvist et al., 2007). The possibility of a role of genetically based metabolic factor was postulated (Lindqvist et al., 2007). The sequence of the metabolism of carotenoids involves the conversion of these hydrocarbons to mono-hydroxy metabolites and to poly-hydroxy metabolites. "
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    ABSTRACT: Hypercarotenaemia is seen more frequently among young infants and children. This condition develops mainly due to excessive intake of carotenoid bearing foods. Evidence shows that, not all infants develop hypercarotenaemia due to excessive intake of carotenoid containing foods. The objective of this study was to study the prevalence of hypercarotenaemia among nursery/kindergarten children in the Western province of Sri Lanka and to correlate the food intake with development of hypercarotenaemia. The occurrence of hypercarotenaemia among their siblings fed similar diets was also observed. A self administrated questionnaire was given to the parents (n = 780) of nursery/kindergarten children (2-5 years) in the Western province to collect information on the intake of carotenoid rich foods and development of hypercarotenaemia among the children attending these nurseries and their siblings. Among all the subjects investigated twelve (n = 12) had developed hypercarotenaemia. Children fed with high carotenoid bearing food/fruits were categorized in to two groups depending on the whether they have received a vitamin A mega dose (n = 287) or not (n = 328). The prevalence of hypercarotenaemia among children fed high quantity of carotenoid foods (n = 615) was 2%, while the group fed with vitamin A mega dose and not fed vitamin A mega dose were 1.4% and 2.5% respectively. We suggest a genetic effect that is probably recessive, involved with absorption or the metabolism of carotenoids in children who develop hypercarotenaemia. In conclusion, the study showed the prevalence of hypercarotenaemia to be <2%, irrespective of the amount of carotenoids ingested and vitamin A mega dosing
    International Food Research Journal 02/2013; 20(4):1873-1875.
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    • "Several mutations have been found in the coding region of BCMO1 gene in humans. One, most likely very rare, leads to a drastic enzyme loss-of-function (90%) and hypercarotenemia and hypovitaminosis A [18]. Others, more frequently distributed also reduce enzyme activity but to a lower extent [19]. "
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    ABSTRACT: Classical quantitative trait loci (QTL) analysis and gene expression QTL (eQTL) were combined to identify the causal gene (or QTG) underlying a highly significant QTL controlling the variation of breast meat color in a F2 cross between divergent high-growth (HG) and low-growth (LG) chicken lines. Within this meat quality QTL, BCMO1 (Accession number GenBank: AJ271386), encoding the β-carotene 15, 15'-monooxygenase, a key enzyme in the conversion of β-carotene into colorless retinal, was a good functional candidate. Analysis of the abundance of BCMO1 mRNA in breast muscle of the HG x LG F2 population allowed for the identification of a strong cis eQTL. Moreover, reevaluation of the color QTL taking BCMO1 mRNA levels as a covariate indicated that BCMO1 mRNA levels entirely explained the variations in meat color. Two fully-linked single nucleotide polymorphisms (SNP) located within the proximal promoter of BCMO1 gene were identified. Haplotype substitution resulted in a marked difference in BCMO1 promoter activity in vitro. The association study in the F2 population revealed a three-fold difference in BCMO1 expression leading to a difference of 1 standard deviation in yellow color between the homozygous birds at this haplotype. This difference in meat yellow color was fully consistent with the difference in carotenoid content (i.e. lutein and zeaxanthin) evidenced between the two alternative haplotypes. A significant association between the haplotype, the level of BCMO1 expression and the yellow color of the meat was also recovered in an unrelated commercial broiler population. The mutation could be of economic importance for poultry production by making possible a gene-assisted selection for color, a determining aspect of meat quality. Moreover, this natural genetic diversity constitutes a new model for the study of β-carotene metabolism which may act upon diverse biological processes as precursor of the vitamin A.
    PLoS ONE 07/2011; 6(7):e14825. DOI:10.1371/journal.pone.0014825 · 3.23 Impact Factor
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    • "Around 25–45% of the volunteers participating in BC conversion studies have been classified as poor converters [11–13]. These inter-individual differences in BC metabolism are at least partly related to polymorphisms in the BCMO1 gene, which results in a reduced BCMO1 activity [14, 15]. Of the reported polymorphisms, there are two frequently occurring polymorphisms with variant allele frequencies of 42 and 24%. "
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    ABSTRACT: Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15'-monooxygenase 1 knockout (Bcmo1 (-/-)) mice, which are-like humans-able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 (-/-) mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 (-/-) mice. Testosterone levels were higher after BC supplementation only in Bcmo1 (-/-) mice, which had, unlike wild-type (Bcmo1 (+/+)) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.
    Cellular and Molecular Life Sciences CMLS 02/2011; 68(3):489-504. DOI:10.1007/s00018-010-0461-0 · 5.81 Impact Factor
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