• PMID: 19116240
• Gene Name: CYP11A1
• Condition: Late-onset�adrenal�insufficiency, hypospadias
• Association: This case represents the mildest phenotype of P450scc�deficiency�to be described. The phenotypic presentation was consistent with the partial reduction of P450scc activity of L222P mutant.
• Mutation: L222P
• Population size: 1
• Population details: 1 patient with late-onset adrenal insufficiency and hypospadias in a 46,XY patient
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Late-onset�adrenal�insufficiency, hypospadias

A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient

Rubtsov P, Karmanov M, Sverdlova P, Spirin P, Tiulpakov A.

CONTEXT: The first and the rate-limiting step in the biosynthesis of hormones in all steroidogenic tissues, conversion of cholesterol to pregnenolone, is catalyzed by the cholesterol side-change cleavage cytochrome P450 (P450scc) encoded by a single gene, CYP11A1. To date, mutations in CYP11A1 gene have been reported in six patients, all of whom presented with adrenal insufficiency within the first 4 yr of life and severely underandrogenized external genitalia (Prader stages 1-2). OBJECTIVE: Our aim was to characterize in vitro and in vivo effects of a novel homozygous CYP11A1 gene mutation identified in a patient with an unusual presentation of P450scc deficiency. METHODS AND PATIENTS: A 46,XY patient presented with mid-shaft hypospadias and cryptorchidism at birth and signs of adrenal failure at 9 yr. Mutational analysis of CYP11A1 gene was performed by PCR, followed by direct sequencing. P450scc activity was determined by measuring concentration of pregnenolone synthesized from cholesterol in the medium after a transient transfection of HEK293 cells with P450scc, adrenodoxin, adrenodoxin reductase, and steroidogenic acute regulatory protein expression plasmids. RESULTS: The sequencing of CYP11A1 gene in the proband revealed a novel homozygous L222P mutation, whereas both parents were heterozygous carriers for this mutation. In vitro P450scc activity of L222P mutant was approximately 7% compared with the wild type. CONCLUSIONS: This case represents the mildest phenotype of P450scc deficiency to be described. The phenotypic presentation was consistent with the partial reduction of P450scc activity of L222P mutant. FAU - Rubtsov, Petr AU - Rubtsov P AD - Department of Endocrine Genetics, Endocrinology Research Center, Moscow 117036, Russian Federation. FAU - Karmanov, Maksim AU - Karmanov M FAU - Sverdlova, Polina AU - Sverdlova P FAU - Spirin, Pavel AU - Spirin P