Abstract
Context: The cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. CYP11A1 mutations are associated with primary adrenal insufficiency (PAI) as well as disorders of sex development (DSD) in 46,XY patients. Objective: To define the pathogenicity mechanism for the p.Glu314Lys variant, previously reported, and found in four additional patients with CYP11A1 deficiency. Subjects and Methods: DNA of four patients presenting with delayed PAI and/or 46,XY DSD were studied by Sanger or Massively Parallel sequencing. Three CYP11A1 mutations were characterized in vitro and in silico, and one by mRNA analysis on testicular tissue. Results: All patients were compound heterozygous for the previously described p.Glu314Lys variant. In silico studies predicted this mutation as benign with no effect on splicing but mRNA analysis found that it led to incomplete exon 5 skipping. This mechanism was confirmed by minigene experiment. The protein carrying this mutation without exon skipping should conserve almost normal activity, according to in vitro studies. Two other mutations found in trans, the p.Arg120Gln and p.Arg465Trp, had similar activity com...Continue Reading
References
Dec 1, 1991·The Journal of Clinical Investigation·D LinW L Miller
Mar 24, 1995·Science·D LinW L Miller
Jun 1, 1993·DNA and Cell Biology·J A HarikrishnaW L Miller
Apr 29, 1998·The Journal of Clinical Endocrinology and Metabolism·W L Miller
Aug 15, 2001·The Journal of Clinical Endocrinology and Metabolism·T TajimaW L Miller
Aug 6, 2002·The Journal of Clinical Endocrinology and Metabolism·Noriyuki KatsumataToshiaki Tanaka
Aug 29, 2003·The Journal of Steroid Biochemistry and Molecular Biology·Kenji FujiedaJun Nakae
Oct 28, 2004·The Journal of Clinical Endocrinology and Metabolism·Olaf HiortDagmar Struve
Oct 4, 2005·Journal of Medical Genetics·D Baralle, M Baralle
May 18, 2006·The Journal of Clinical Endocrinology and Metabolism·Hessa al KandariMajedah Abdul Rasoul
Jan 10, 2008·The Journal of Clinical Endocrinology and Metabolism·Chan Jong KimWalter L Miller
Jan 1, 2009·The Journal of Clinical Endocrinology and Metabolism·Petr RubtsovAnatoly Tiulpakov
Dec 17, 2010·The Journal of Clinical Endocrinology and Metabolism·Taninee SahakitrungruangWalter L Miller
Mar 11, 2011·The New England Journal of Medicine·Tamas Zakar, Sam Mesiano
Sep 2, 2011·The Journal of Clinical Endocrinology and Metabolism·Silvia ParajesNils Krone
Sep 13, 2012·European Journal of Endocrinology·Silvia ParajesNils Krone
Jan 23, 2013·The Journal of Clinical Endocrinology and Metabolism·Meng Kian TeeWalter L Miller
Mar 6, 2015·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Sue RichardsUNKNOWN ACMG Laboratory Quality Assurance Committee
Apr 8, 2015·DNA and Cell Biology·Gilles MillatDominique Bozon
Aug 25, 2015·Frontiers in Endocrinology·Li F ChanLouise A Metherell
Nov 3, 2015·The Journal of Clinical Endocrinology and Metabolism·Tulay GuranJohn C Achermann
Mar 10, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Walter L Miller
Mar 24, 2016·Journal of Pediatric Endocrinology & Metabolism : JPEM·Renata PomahačováEva Dortová
May 1, 2016·European Journal of Endocrinology·Florence Roucher-BoulezYves Morel
Nov 18, 2016·Endocrinology, Diabetes & Metabolism Case Reports·Jasmeet KaurHimangshu S Bose
Nov 28, 2017·Molecular Genetics & Genomic Medicine·Montserrat Lara-VelazquezPaldeep S Atwal
Jan 5, 2018·Genes·Lorena Suarez-ArtilesFelix Claverie-Martin
Citations
Oct 15, 2019·Clinical Endocrinology·Federica Buonocore, John C Achermann
Dec 1, 2018·The Journal of Clinical Endocrinology and Metabolism·Florence Roucher-BoulezYves Morel
Dec 1, 2018·The Journal of Clinical Endocrinology and Metabolism·Vipula KolliDeborah P Merke
Jul 11, 2019·BMJ Case Reports·Vijaya Sarathi, Chithambaram Nagalingam
Mar 16, 2021·Molecular and Cellular Endocrinology·R M SlominskiR C Tuckey
Jul 15, 2021·Journal of the Endocrine Society·Federica BuonocoreJohn C Achermann
Sep 1, 2021·Orphanet Journal of Rare Diseases·Bingqing YuXueyan Wu