eprintid: 105474 rev_number: 63 eprint_status: archive userid: 608 dir: disk0/00/10/54/74 datestamp: 2010-10-20 08:15:18 lastmod: 2021-12-13 01:52:36 status_changed: 2013-07-08 11:23:12 type: article metadata_visibility: show item_issues_count: 0 creators_name: Kim, CJ creators_name: Lin, L creators_name: Huang, NW creators_name: Quigley, CA creators_name: AvRuskin, TW creators_name: Achermann, JC creators_name: Miller, WL title: Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G23 keywords: ACUTE-REGULATORY-PROTEIN, STEROIDOGENIC FACTOR-I, 20,22 DESMOLASE DEFICIENCY, 46,XY SEX REVERSAL, HYPOPLASIA CONGENITA, ADRENODOXIN REDUCTASE, DAX-1 GENE, HYPERPLASIA, PATIENT, CYP11A1 note: © 2008 by The Endocrine Society abstract: Context: Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues. Although progesterone production from the fetally-derived placenta is necessary to maintain pregnancy to term, four patients with mutations in the gene encoding P450scc (CYP11A1), have been described, one in a 46, XX female and three in underandrogenized 46,XY individuals, all with primary adrenal failure.Objective: Our aim was to determine whether P450scc mutations might be found in other children and to explore genotype/phenotype correlations.Methods and Patients: We performed mutational analysis of CYP11A1 in individuals with 46, XY disorders of sex development and primary adrenal failure, followed by functional studies of P450scc activity and of P450scc RNA splicing.Results: Among nine 46, XY infants with adrenal failure and disordered sexual differentiation, two infants had compound heterozygous mutations in CYP11A1. One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38 and 0% activity, respectively. The other carried a CYP11A1 frameshift mutation c835delA ( 0% activity) and a splice site mutation [IVS3 +(2-3) insT] that prevented correct splicing of P450scc mRNA.Conclusions: P450scc deficiency is a recently recognized disorder that may be more frequent than originally thought. The phenotypic spectrum ranges from severe loss-of-function mutations associated with prematurity, complete underandrogenization, and severe, early-onset adrenal failure, to partial deficiencies found in children born at term with clitoromegaly and later-onset adrenal failure. In contradistinction to congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein mutations, adrenal hyperplasia has not been reported in any of the six patients with P450scc deficiency. date: 2008-03 publisher: ENDOCRINE SOC official_url: http://dx.doi.org/10.1210/jc.2007-2330 oa_status: green language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_batch elements_source: Web of Science elements_id: 102364 doi: 10.1210/jc.2007-2330 language_elements: EN lyricists_name: Achermann, John lyricists_id: JCACH11 full_text_status: public publication: The Journal of Clinical Endocrinology & Metabolism volume: 93 number: 3 pagerange: 696 - 702 issn: 0021-972X citation: Kim, CJ; Lin, L; Huang, NW; Quigley, CA; AvRuskin, TW; Achermann, JC; Miller, WL; (2008) Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. The Journal of Clinical Endocrinology & Metabolism , 93 (3) 696 - 702. 10.1210/jc.2007-2330 <https://doi.org/10.1210/jc.2007-2330>. Green open access document_url: https://discovery-pp.ucl.ac.uk/id/eprint/105474/1/696.full.pdf