{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:23:35Z","timestamp":1790389415204,"version":"4.1.0"},"reference-count":34,"publisher":"The Endocrine Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Context: The steroidogenic acute regulatory protein (StAR) has been shown to be essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause the typical clinical picture of congenital lipoid adrenal hyperplasia.<\/jats:p>\n                  <jats:p>Objective: The objective of the investigation was to study the functional and structural consequences of three novel StAR mutations (p.N148K in an Italian patient; p.P129fs and p.Q128R in a Turkish patient).<\/jats:p>\n                  <jats:p>Methods and Results: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.N148K mutant, the combined p.P129fs and p.Q128R mutant, and the p.P129fs mutant by itself. The p.Q128R mutant led to a higher cholesterol conversion than the wild-type StAR protein. As derived from three-dimensional protein modeling, the residue N148 is lining the ligand cavity of StAR. A positively charged lysine residue at position 148 disturbs the hydrophobic cluster formed by the \u03b14-helix and the sterol binding pocket. The frame shift mutation p.P129fs truncates the StAR protein. Residue p.Q128 is situated at the surface of the molecule and is not part of any functionally characterized region of the protein.<\/jats:p>\n                  <jats:p>Conclusion: The mutations p.N148K and p.P129fs cause adrenal insufficiency in both cases and lead to a disorder of sex development with complete sex reversal in the 46, XY case. The mutation p.Q128R, which is not relevant for the patient\u2019s phenotype, is the first reported variant showing a gain of function. We speculate that the substitution of hydrophilic glutamine with basic arginine at the surface of the molecule may accelerate cholesterol transfer.<\/jats:p>","DOI":"10.1210\/jc.2009-1176","type":"journal-article","created":{"date-parts":[[2010,1,15]],"date-time":"2010-01-15T20:35:17Z","timestamp":1263587717000},"page":"1301-1308","source":"Crossref","is-referenced-by-count":28,"title":["Congenital Lipoid Adrenal Hyperplasia: Functional Characterization of Three Novel Mutations in the STAR Gene"],"prefix":"10.1210","volume":"95","author":[{"given":"Susanne","family":"Bens","sequence":"first","affiliation":[{"name":"Department of Pediatrics (S.B., A.E.K., P.-M.H., F.G.R.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Mohn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (A.M., F.C.), University of Chieti, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilgin","family":"Yu\u0308ksel","sequence":"additional","affiliation":[{"name":"Cukurova University, Division of Pediatric Endocrinology and Metabolism (B.Y., M.N.O.), 01330 Balcali\/Adana, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Kulle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (S.B., A.E.K., P.-M.H., F.G.R.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Michalek","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry (M.M., J.G.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Chiarelli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (A.M., F.C.), University of Chieti, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Nuri O\u0308zbek","sequence":"additional","affiliation":[{"name":"Cukurova University, Division of Pediatric Endocrinology and Metabolism (B.Y., M.N.O.), 01330 Balcali\/Adana, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Leuschner","sequence":"additional","affiliation":[{"name":"Department of Pathology (I.L.), Division of Paidopathology, Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Gro\u0308tzinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry (M.M., J.G.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul-Martin","family":"Holterhus","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (S.B., A.E.K., P.-M.H., F.G.R.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix G.","family":"Riepe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (S.B., A.E.K., P.-M.H., F.G.R.), Christian-Albrechts-University, D-24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071613262100300_R1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0960-0760(98)00153-8","article-title":"Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR","volume":"69","author":"Miller","year":"1999","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2020071613262100300_R2","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1210\/jc.2006-1565","article-title":"Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia","volume":"91","author":"Baker","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R3","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1126\/science.7892608","article-title":"Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis","volume":"267","author":"Lin","year":"1995","journal-title":"Science"},{"key":"2020071613262100300_R4","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1056\/NEJM199612193352503","article-title":"The pathophysiology and genetics of congenital lipoid adrenal hyperplasia","volume":"335","author":"Bose","year":"1996","journal-title":"N Engl J Med"},{"key":"2020071613262100300_R5","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1093\/hmg\/6.4.571","article-title":"Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia","volume":"6","author":"Nakae","year":"1997","journal-title":"Hum Mol Genet"},{"key":"2020071613262100300_R6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1080\/10408369991239222","article-title":"Congenital adrenal hyperplasia: molecular genetics and alternative approaches to treatment","volume":"36","author":"Stratakis","year":"1999","journal-title":"Crit Rev Clin Lab Sci"},{"key":"2020071613262100300_R7","doi-asserted-by":"crossref","first-page":"6303","DOI":"10.1210\/jc.2005-0434","article-title":"Phenotypic features associated with mutations in steroidogenic acute regulatory protein","volume":"90","author":"Bhangoo","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R8","doi-asserted-by":"crossref","first-page":"28314","DOI":"10.1016\/S0021-9258(18)46930-X","article-title":"The purification, cloning, and expression of a novel LH-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)","volume":"269","author":"Clark","year":"1994","journal-title":"J Biol Chem"},{"key":"2020071613262100300_R9","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.bbalip.2007.02.012","article-title":"Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter","volume":"1771","author":"Miller","year":"2007","journal-title":"Biochim Biophys Acta"},{"key":"2020071613262100300_R10","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1172\/JCI119284","article-title":"Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivity mutations in the steroidogenic acute regulatory protein (StAR) gene","volume":"99","author":"Fujieda","year":"1997","journal-title":"J Clin Invest"},{"key":"2020071613262100300_R11","first-page":"1511","article-title":"Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein","volume":"82","author":"Bose","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R12","doi-asserted-by":"crossref","first-page":"11540","DOI":"10.1073\/pnas.94.21.11540","article-title":"Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights in congenital lipoid adrenal hyperplasia","volume":"94","author":"Caron","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613262100300_R13","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1210\/mend.14.9.0515","article-title":"Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice","volume":"14","author":"Hasegawa","year":"2000","journal-title":"Mol Endocrinol"},{"key":"2020071613262100300_R14","doi-asserted-by":"crossref","first-page":"12506","DOI":"10.1021\/bi00039a004","article-title":"Structure of the human steroidogenic acute regulatory protein (StAR) gene: StAR stimulates mitochondrial cholesterol 27-hydroxylase activity","volume":"34","author":"Sugawara","year":"1995","journal-title":"Biochemistry"},{"key":"2020071613262100300_R15","doi-asserted-by":"crossref","first-page":"13731","DOI":"10.1073\/pnas.93.24.13731","article-title":"Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action","volume":"93","author":"Arakane","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613262100300_R16","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1210\/endo.139.9.6204","article-title":"Effect of truncated forms of the steroidogenic acute regulatory protein on intramitochondrial cholesterol transfer","volume":"139","author":"Wang","year":"1998","journal-title":"Endocrinology"},{"key":"2020071613262100300_R17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O","article-title":"Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group","volume":"11","author":"Antonarakis","year":"1998","journal-title":"Hum Mutat"},{"key":"2020071613262100300_R18","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1210\/endo.131.6.1446636","article-title":"Regulation of human cytochrome P450scc and adrenodoxin messenger ribonucleic acids in JEG-3 cytotrophoblast cells","volume":"131","author":"Brentano","year":"1992","journal-title":"Endocrinology"},{"key":"2020071613262100300_R19","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1073\/pnas.89.9.4099","article-title":"cAMP post-transcriptionally diminishes the abundance of adrenodoxin reductase mRNA","volume":"89","author":"Brentano","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613262100300_R20","doi-asserted-by":"crossref","first-page":"4976","DOI":"10.1210\/jc.2006-0777","article-title":"Four novel missense mutations in the CYP21A2 gene detected in Russian patients suffering from the classical form of congenital adrenal hyperplasia: identification, functional characterization, and structural analysis","volume":"91","author":"Grischuk","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R21","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1210\/en.2003-1034","article-title":"Molten globule structure and steroidogenic activity of N-218 MLN64 in human placental mitochondria","volume":"145","author":"Tuckey","year":"2004","journal-title":"Endocrinology"},{"key":"2020071613262100300_R22","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1006\/geno.1995.1163","article-title":"Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11\u2013q21.3 region of chromosome 17","volume":"28","author":"Tomasetto","year":"1995","journal-title":"Genomics"},{"key":"2020071613262100300_R23","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/75192","article-title":"Structure and lipid transport mechanism of a StAR-related domain","volume":"7","author":"Tsujishita","year":"2000","journal-title":"Nat Struct Biol"},{"key":"2020071613262100300_R24","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1194\/jlr.M600232-JLR200","article-title":"Modeling the structure of the START domains of MLN64 and StAR proteins in complex with cholesterol","volume":"47","author":"Murcia","year":"2006","journal-title":"J Lipid Res"},{"key":"2020071613262100300_R25","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1107\/S0021889891004399","article-title":"MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures","volume":"24","author":"Kraulis","year":"1991","journal-title":"J Appl Crystallogr"},{"key":"2020071613262100300_R26","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1210\/jc.2004-1323","article-title":"A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings","volume":"90","author":"Chen","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R27","first-page":"3636","article-title":"Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia","volume":"85","author":"Bose","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613262100300_R28","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1242\/jcs.02485","article-title":"Give lipids a START: the StAR-related lipid transfer (START) domain in mammals","volume":"118","author":"Alpy","year":"2005","journal-title":"J Cell Sci"},{"key":"2020071613262100300_R29","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"Clustal W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res"},{"key":"2020071613262100300_R30","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1677\/jme.0.0290327","article-title":"Insights into steroidogenic acute regulatory protein (StAR)-dependent cholesterol transfer in mitochondria: evidence from molecular modeling and structure-based thermodynamics supporting the existence of partially unfolded states of StAR","volume":"29","author":"Mathieu","year":"2002","journal-title":"J Mol Endocrinol"},{"key":"2020071613262100300_R31","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1074\/jbc.M410937200","article-title":"pH-dependent Interactions of the carboxyl-terminal helix of steroidogenic acute regulatory protein with synthetic membranes","volume":"280","author":"Yaworsky","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071613262100300_R32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.mce.2008.12.007","article-title":"Toward the NMR structure of StAR","volume":"300","author":"Barbar","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"2020071613262100300_R33","doi-asserted-by":"crossref","first-page":"10223","DOI":"10.1074\/jbc.M611221200","article-title":"Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR","volume":"282","author":"Baker","year":"2007","journal-title":"J Biol Chem"},{"key":"2020071613262100300_R34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1042\/BSR20080111","article-title":"The mechanism of specific binding of free cholesterol by the steroidogenic acute regulatory protein: evidence for a role of the C-terminal \u03b1-helix in the gating of the binding site","volume":"29","author":"Roostaee","year":"2009","journal-title":"Biosci Rep"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/95\/3\/1301\/9067645\/jcem1301.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/95\/3\/1301\/9067645\/jcem1301.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T07:15:53Z","timestamp":1634714153000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/95\/3\/1301\/2597250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,1]]},"references-count":34,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2010,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2009-1176","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,3,1]]}}}