Journal article
Varied Clinical Presentations of Seven Patients With Mutations in CYP11A1 Encoding the Cholesterol Side-Chain Cleavage Enzyme, P450scc
The journal of clinical endocrinology and metabolism, Vol.98(2), pp.713-720
2013
DOI: 10.1210/jc.2012-2828
PMCID: PMC3565115
PMID: 23337730
Abstract
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: Wesequenced 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 cellswere 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.
Details
- Title: Subtitle
- Varied Clinical Presentations of Seven Patients With Mutations in CYP11A1 Encoding the Cholesterol Side-Chain Cleavage Enzyme, P450scc
- Creators
- Meng Kian Tee - Department of Pediatrics University of California, San Francisco, San Francisco, California, 94143, United StatesMichal ABRAMSOHN - Department of Developmental Genetics and Virology, IsraelEli HERSHKOVITZ - Faculty of Health Sciences and the National Institute of Biotechnology Negev, and Pediatric Endocrinology Unit Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, IsraelWalter L MILLER - Department of Pediatrics University of California, San Francisco, San Francisco, California, 94143, United StatesNeta LOEWENTHAL - Faculty of Health Sciences and the National Institute of Biotechnology Negev, and Pediatric Endocrinology Unit Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, IsraelMark HARRIS - Department of Pediatric Endocrinology Mater Children's Hospital, Brisbane, Queensland 4101, AustraliaSudeep SIWACH - Department of Pediatric Endocrinology Mater Children's Hospital, Brisbane, Queensland 4101, AustraliaAna KAPLINSKY - Faculty of Health Sciences and the National Institute of Biotechnology Negev, and Pediatric Endocrinology Unit Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, IsraelBarak MARKUS - Department of Developmental Genetics and Virology, IsraelOhad BIRK - Department of Developmental Genetics and Virology, IsraelVal C SHEFFIELD - Howard Hughes Medical Institute University of Iowa, Iowa City, Iowa 52242, United StatesRuti PAVARI - Department of Developmental Genetics and Virology, Israel
- Resource Type
- Journal article
- Publication Details
- The journal of clinical endocrinology and metabolism, Vol.98(2), pp.713-720
- Publisher
- Endocrine Society; Bethesda, MD
- DOI
- 10.1210/jc.2012-2828
- PMID
- 23337730
- PMCID
- PMC3565115
- ISSN
- 0021-972X
- eISSN
- 1945-7197
- Language
- English
- Date published
- 2013
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984065483602771
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