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Cited by 82Adrenal Hormones and DisordersSexual Differentiation and DisordersMetabolism and Genetic Disorders

A Novel Homozygous Mutation in CYP11A1 Gene Is Associated with Late-Onset Adrenal Insufficiency and Hypospadias in a 46,XY Patient

Rubtsov, Petr, Karmanov, Maksim, Sverdlova, Polina, Spirin, Pavel, Tiulpakov, Anatoly·2009·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2008-1118
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Abstract

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.

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  • Mild or nonclassic P450scc deficiency has been reported in patients carrying P450scc mutations that retain about 10-20% of wild-type activity.

    “Mild or nonclassic P450scc deficiency has been reported recently in patients carrying P450scc mutations that retain about 10 -20% of wild-type activity (156,157).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [156]

    The Discussion (p. 3) describes this patient's late-onset, relatively mild P450scc deficiency, but reports that the L222P mutation retained 6.9% of normal activity—not about 10–20%. It also mentions another mutation with 11.7% activity, but that patient developed adrenal insufficiency much earlier, at 21 months. (LLM, conf=0.90)

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Authors
Rubtsov, P., Karmanov, M., Sverdlova, P., Spirin, P., & Tiulpakov, A.
Affiliations
  • Engelhardt Institute of Molecular Biology (P.R., P.Sv., P.Sp.), Moscow 119991, Russian Federation
  • Russian Children's Clinical Hospital (RU)
  • Engelhardt Institute of Molecular Biology (RU)
  • Endocrinology Research Center (RU)
Corresponding author
Tiulpakov, Anatoly
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2009-03-01
Volume
94
Issue
3
Pages
936-939
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2008-1118
OpenAlex
W1988874431
Semantic Scholar
3f27b40065e5c80ecc4406a71b0a4e45cc5cae39
Cited by
82
References
21
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 6
FWCI
3.14
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
CYP11A1, hypospadias, cryptorchidism, 46,XY disorders of sex development, cholesterol side-chain cleavage, pregnenolone synthesis, steroidogenesis, genotype-phenotype correlation
MeSH terms
Steroidogenic Acute Regulatory Protein, Adrenal Insufficiency, Child, Cholesterol Side-Chain Cleavage Enzyme, Gonadal Dysgenesis, 46,XY, Homozygote, Humans, Hypospadias, Male, Mutation, Phosphoproteins

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