Varied Clinical Presentations of Seven Patients With Mutations in CYP11A1 Encoding the Cholesterol Side-Chain Cleavage Enzyme, P450scc
Open accessAbstract
CONTEXT: The cholesterol side-chain cleavage enzyme P450scc, encoded by CYP11A1, converts cholesterol to pregnenolone to initiate steroidogenesis. P450scc deficiency can disrupt adrenal and gonadal steroidogenesis, resembling congenital lipoid adrenal hyperplasia clinically and hormonally; only 12 such patients have been reported previously. OBJECTIVE: We sought to expand clinical and genetic experience with P450scc deficiency. PATIENTS AND METHODS: We sequenced candidate genes in 7 children with adrenal insufficiency who lacked disordered sexual development. P450scc missense mutations were recreated in the F2 vector, which expresses the fusion protein P450scc-Ferredoxin Reductase-Ferredoxin. COS-1 cells were transfected, production of pregnenolone was assayed, and apparent kinetic parameters were calculated. Previously described P450scc mutants were assayed in parallel. RESULTS: Four of five Bedouin children in one kindred were compound heterozygotes for mutations c.694C>T (Arg232Stop) and c.644T>C (Phe215Ser). Single-nucleotide polymorphism analysis confirmed segregation of these mutations. The fifth kindred member and another Bedouin patient presented in infancy and were homozygous for Arg232Stop. A patient from Fiji presenting in infancy was homozygous for c.358T>C (Arg120Stop). All mutations are novel. As assayed in the F2 fusion protein, P450scc Phe215Ser retained 2.5% of wild-type activity; previously described mutants Leu141Trp and Ala269Val had 2.6% and 12% of wild-type activity, respectively, and Val415Glu and c.835delA lacked detectable activity. CONCLUSIONS: Although P450scc is required to produce placental progesterone required to maintain pregnancy, severe mutations in P450scc are compatible with term gestation; milder P450scc mutations may present later without disordered sexual development. Enlarged adrenals usually distinguish steroidogenic acute regulatory protein deficiency from P450scc deficiency, but only DNA sequencing is definitive.
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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 [51]
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458 · see citing works
Self-citationRole of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis
Lin, D., Sugawara, T., Strauss, J. F., Clark, B. J., Stocco, D. M., Saenger, P., Rogol, A., & Miller, W. L. (1995) · Science · doi:10.1126/science.7892608 · Cited by 1,030 · see citing works
Self-citationThe pathophysiology and genetics of congenital lipoid adrenal hyperplasia
Bose, H. S., Sugawara, T., Strauss, J. F., & Miller, W. L. (1996) · New England Journal of Medicine · doi:10.1056/nejm199612193352503 · Cited by 676 · see citing works
Self-citationEffects of luteectomy and progesterone replacement therapy in early pregnant patients
Csapo, A. I., Pulkkinen, M. O., & Wiest, W. G. (1973) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(73)90517-6 · Cited by 401 · see citing works
Chung, B. C., Matteson, K. J., Voutilainen, R., Mohandas, T. K., & Miller, W. L. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.23.8962 · Cited by 354 · see citing works
Self-citationStructural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system
Strushkevich, N., MacKenzie, F., Cherkesova, T., Grabovec, I., Usanov, S., & Park, H.-W. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019441108 · Cited by 337 · see citing works
Csapo, A. I., & PULKKINEN, M. O. (1978) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-197802000-00001 · Cited by 313 · see citing works
Miller, W. L. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0303 · Cited by 209 · see citing works
Self-citationTajima, T., Fujieda, K., Kouda, N., Nakae, J., & Miller, W. L. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.8.7748 · Cited by 196 · see citing works
Self-citationBaker, B. Y., Lin, L., Kim, C. J., Raza, J., Smith, C. P., Miller, W. L., & Achermann, J. C. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1565 · Cited by 194 · see citing works
Self-citationFujieda, K., Tajima, T., Nakae, J., Sageshima, S., Tachibana, K., Suwa, S., Sugawara, T., & Strauss, J. F. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119284 · Cited by 162 · see citing works
Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency
Metherell, L. A., Naville, D., Halaby, G., Begeot, M., Huebner, A., Nürnberg, G., Nürnberg, P., Green, J., Tomlinson, J. W., Krone, N. P., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0467 · Cited by 162 · see citing works
Bose, H. S., Pescovitz, O. H., & Miller, W. L. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.5.3962 · Cited by 160 · see citing works
Self-citationSteroid deficiency syndromes in mice with targeted disruption of Cyp11a1
Hu, M.-C., Hsu, N.-C., El Hadj, N. B., Pai, C.-I., Chu, H.-P., Wang, C.-K. L., & Chung, B.-C. (2002) · Molecular Endocrinology · doi:10.1210/me.2002-0055 · Cited by 153 · see citing works
Construction and function of fusion enzymes of the human cytochrome P450scc system
HARIKRISHNA, J. A., BLACK, S. M., SZKLARZ, G. D., & MILLER, W. L. (1993) · DNA and Cell Biology · doi:10.1089/dna.1993.12.371 · Cited by 141 · see citing works
Self-citationKim, C. J., Lin, L., Huang, N., Quigley, C. A., AvRuskin, T. W., Achermann, J. C., & Miller, W. L. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2330 · Cited by 139 · see citing works
Self-citationMast, N., Annalora, A. J., Lodowski, D. T., Palczewski, K., Stout, C. D., & Pikuleva, I. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.188433 · Cited by 138 · see citing works
Bose, H. S., Sato, S., Aisenberg, J., Shalev, S. A., Matsuo, N., & Miller, W. L. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.10.6896 · Cited by 131 · see citing works
Self-citationKatsumata, N., Ohtake, M., Hojo, T., Ogawa, E., Hara, T., Sato, N., & Tanaka, T. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.8.8763 · Cited by 125 · see citing works
Hiort, O., Holterhus, P.-M., Werner, R., Marschke, C., Hoppe, U., Partsch, C.-J., Riepe, F. G., Achermann, J. C., & Struve, D. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1059 · Cited by 120 · see citing works
Sahakitrungruang, T., Tee, M. K., Blackett, P. R., & Miller, W. L. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1828 · Cited by 111 · see citing works
Self-citationRubtsov, P., Karmanov, M., Sverdlova, P., Spirin, P., & Tiulpakov, A. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1118 · Cited by 82 · see citing works
Yang, X., Iwamoto, K., Wang, M., Artwohl, J., Mason, J. I., & Pang, S. (1993) · Endocrinology · doi:10.1210/endo.132.5.7682938 · Cited by 73 · see citing works
al Kandari, H., Katsumata, N., Alexander, S., & Rasoul, M. A. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2230 · Cited by 68 · see citing works
Parajes, S., Kamrath, C., Rose, I. T., Taylor, A. E., Mooij, C. F., Dhir, V., Grötzinger, J., Arlt, W., & Krone, N. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1277 · Cited by 59 · see citing works
Regulation of proteins in the cholesterol side-chain cleavage system in JEG-3 and Y-1 cells
Black, S. M., Szklarz, G. D., Harikrishna, J. A., Lin, D., Wolf, C. R., & Miller, W. L. (1993) · Endocrinology · doi:10.1210/endo.132.2.8425475 · Cited by 58 · see citing works
Self-citationParajes, S., Chan, A. O., But, W. M., Rose, I., TAYLOR, A. E. R., Dhir, V., Arlt, W., & Krone, N. P. (2012) · European Journal of Endocrinology · doi:10.1530/eje-12-0450 · Cited by 30 · see citing works
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Morel, Y., Roucher, F., Plotton, I., Goursaud, C., Tardy, V., & Mallet, D. (2016) · Annales d'Endocrinologie · doi:10.1016/j.ando.2016.04.023 · Cited by 119 · see citing works
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Baranowski, E. S., Arlt, W., & Idkowiak, J. (2018) · Hormone Research in Paediatrics · doi:10.1159/000488034 · Cited by 79 · see citing works
- Authors
- Tee, M. K., Abramsohn, M., Loewenthal, N., Harris, M., Siwach, S., Kaplinsky, A., Markus, B., Birk, O., Sheffield, V. C., Pavari, R., Hershkovitz, E., & Miller, W. L.
- Affiliations
- University of California, San Francisco (US)
- Ben-Gurion University of the Negev (IL)
- Mater Children's Hospital (AU)
- University of Iowa (US)
- Corresponding author
- Miller, Walter L.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2013-02
- Volume
- 98
- Issue
- 2
- Pages
- 713-720
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3565115
- OpenAlex
- W2029142094
- Cited by
- 89
- References
- 27
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 24 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 6 · 2013: 3
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, 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, cholesterol side-chain cleavage enzyme, congenital lipoid adrenal hyperplasia, adrenal insufficiency, steroidogenesis, missense mutations, compound heterozygosity, enzyme activity, pregnancy maintenance
- MeSH terms
- Adrenal Insufficiency, Animals, Chlorocebus aethiops, Child, Preschool, Cholesterol Side-Chain Cleavage Enzyme, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Phenotype, COS Cells
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