Partial Defect in the Cholesterol Side-Chain Cleavage Enzyme P450scc (CYP11A1) Resembling Nonclassic Congenital Lipoid Adrenal Hyperplasia
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CONTEXT: The cholesterol side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene, converts cholesterol to pregnenolone to initiate steroidogenesis. Genetic defects in P450scc cause a rare autosomal recessive disorder that is clinically indistinguishable from congenital lipoid adrenal hyperplasia (lipoid CAH). Nonclassic lipoid CAH is a recently recognized disorder caused by mutations in the steroidogenic acute regulatory protein (StAR) that retain partial function. OBJECTIVE: We describe two siblings with hormonal findings suggesting nonclassic lipoid CAH, who had a P450scc mutation that retains partial function. PATIENTS AND METHODS: A 46,XY male presented with underdeveloped genitalia and partial adrenal insufficiency; his 46,XX sister presented with adrenal insufficiency. Hormonal studies suggested nonclassic lipoid CAH. Sequencing of the StAR gene was normal, but compound heterozygous mutations were found in the CYP11A1 gene. Mutations were recreated in the F2 plasmid expressing a fusion protein of the cholesterol side-chain cleavage system. P450scc activity was measured as Vmax/Km for pregnenolone production in transfected COS-1 cells. RESULTS: The patients were compound heterozygous for the previously described frameshift mutation 835delA and the novel missense mutation A269V. When expressed in the P450scc moiety of F2, the A269V mutant retained 11% activity of the wild-type F2 protein. CONCLUSIONS: There is a broad clinical spectrum of P450scc deficiency. Partial loss-of-function CYP11A1 mutation can present with a hormonal phenotype indistinguishable from nonclassic lipoid CAH.
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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 [157]
The pathogenesis of lipoid CAH is explained by a two-hit model: first, loss of StAR leads to the accumulation of intracellular cholesterol and cholesterol esters, and the second hit arises from destruction of the cellular function by the accumulated products.
“The pathogenesis of lipoid CAH is explained by a two-hit model: first, loss of StAR leads to the accumulation of intracellular cholesterol and cholesterol esters, and the second hit arises from destruction of the cellular function by the accumulated products.48,50,51”
From Congenital adrenal hyperplasia (2017) · cites this paper as [50]
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Self-citation
- Authors
- Sahakitrungruang, T., Tee, M. K., Blackett, P. R., & Miller, W. L.
- Affiliations
- University of California, San Francisco (US)
- University of Oklahoma Health Sciences Center (US)
- Corresponding author
- Miller, Walter L.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2011-03-01
- Volume
- 96
- Issue
- 3
- Pages
- 792-798
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3047228
- OpenAlex
- W2094557907
- Cited by
- 111
- References
- 43
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 7
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5t32dk007161-48)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, T32-DK-007161, R01DK037922)
- 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, P450scc, cholesterol side-chain cleavage enzyme, congenital lipoid adrenal hyperplasia, compound heterozygosity, steroidogenesis, adrenal insufficiency, 46,XY disorders of sex development, enzyme activity assay, steroidogenic acute regulatory protein
- MeSH terms
- Adrenal Hyperplasia, Congenital, Amino Acid Sequence, Animals, Anti-Inflammatory Agents, Cell Line, Chlorocebus aethiops, Child, Child, Preschool, Cholesterol Side-Chain Cleavage Enzyme, Cryptorchidism, DNA, DNA Mutational Analysis, Female, Genetic Vectors, Gonadal Dysgenesis, 46,XY, Humans, Hydrocortisone, Kinetics, Male, Molecular Sequence Data, Mutation, Frameshift Mutation, COS Cells, Mutation, Missense, Gonadal Dysgenesis, 46,XX
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