CYP3A4 mutation causes vitamin D-dependent rickets type 3.
J Clin Invest
; 128(5): 1913-1918, 2018 05 01.
Article
en En
| MEDLINE
| ID: mdl-29461981
ABSTRACT
Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Raquitismo
/
Vitamina D
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Calcitriol
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Citocromo P-450 CYP3A
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Exoma
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Mutación
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Clin Invest
Año:
2018
Tipo del documento:
Article