{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T20:24:38Z","timestamp":1774643078300,"version":"3.50.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":["jsm.jsexmed.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Mutations in the HSD17B3 gene are associated with a 46,XY disorder of sexual development (46,XY DSD) as a result of low testosterone production during embryogenesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Aim<\/jats:title>\n                  <jats:p>To elucidate the molecular basis of the disorder by chemically analyzing four missense mutations in HSD17B3 (T54A, M164T, L194P, G289S) from Egyptian patients with 46,XY DSD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Expression plasmids for wild-type 17\u03b2-hydroxysteroid hydrogenase type 3 (17\u03b2-HSD3) and mutant enzymes generated by site-directed mutagenesis were transiently transfected into human HEK-293 cells. Protein expression was verified by western blotting and activity was determined by measuring the conversion of radiolabeled \u03944-androstene-3,17-dione to testosterone. Application of a homology model provided an explanation for the observed effects of the mutations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Outcomes<\/jats:title>\n                  <jats:p>Testosterone formation by wild-type and mutant 17\u03b2-HSD3 enzymes was compared.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Mutations T54A and L194P, despite normal protein expression, completely abolished 17\u03b2-HSD3 activity, explaining their severe 46,XY DSD phenotype. Mutant M164T could still produce testosterone, albeit with significantly lower activity compared with wild-type 17\u03b2-HSD3, resulting in ambiguous genitalia or a microphallus at birth. The substitution G289S represented a polymorphism exhibiting comparable activity to wild-type 17\u03b2-HSD3. Sequencing of the SRD5A2 gene in three siblings bearing the HSD17B3 G289S polymorphism disclosed the homozygous Y91H mutation in the former gene, thus explaining the 46,XY DSD presentations. Molecular modeling analyses supported the biochemical observations and predicted a disruption of cofactor binding by mutations T54A and M164T and of substrate binding by L196P, resulting in the loss of enzyme activity. In contrast, the G289S substitution was predicted to disturb neither the three-dimensional structure nor enzyme activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Translation<\/jats:title>\n                  <jats:p>Biochemical analysis of mutant 17\u03b2-HSD3 enzymes is necessary to understand genotype-phenotype relationships.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Strengths and Limitations<\/jats:title>\n                  <jats:p>Biochemical analysis combined with molecular modeling provides insight into disease mechanism. However, the stability of mutant proteins in\u00a0vivo cannot be predicted by this approach.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The 17\u03b2-HSD3 G289S substitution, previously reported in other patients with 46,XY DSD, is a polymorphism that does not cause the disorder; thus, further sequence analysis was required and disclosed a mutation in SRD5A2, explaining the cause of 46,XY DSD in these patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1016\/j.jsxm.2017.07.006","type":"journal-article","created":{"date-parts":[[2017,8,30]],"date-time":"2017-08-30T13:18:12Z","timestamp":1504099092000},"page":"1165-1174","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":10,"title":["Biochemical Analysis of Four Missense Mutations in the <i>HSD17B3<\/i> Gene Associated with 46, XY Disorders of Sex Development in Egyptian Patients"],"prefix":"10.1093","volume":"14","author":[{"given":"Roger T.","family":"Engeli","sequence":"first","affiliation":[{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel , Basel , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Tsachaki","sequence":"additional","affiliation":[{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel , Basel , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heba A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Center , Cairo , Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph P.","family":"Sager","sequence":"additional","affiliation":[{"name":"Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel , Basel , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mona L.","family":"Essawi","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Center , Cairo , Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yehia Z.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Center , Cairo , Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa K.","family":"Kamel","sequence":"additional","affiliation":[{"name":"Department of Human Cytogenetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Center , Cairo , Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inas","family":"Mazen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Center , Cairo , Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Odermatt","sequence":"additional","affiliation":[{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel , Basel , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,9,1]]},"reference":[{"key":"2023011111055478900_bib1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1210\/mend-4-2-268","article-title":"Structure of two in tandem human 17 beta-hydroxysteroid dehydrogenase genes","volume":"4","author":"Luu-The","year":"1990","journal-title":"Mol Endocrinol"},{"key":"2023011111055478900_bib2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0039-128X(86)90038-3","article-title":"Testicular 17 beta-hydroxysteroid dehydrogenase: molecular properties and reaction mechanism","volume":"48","author":"Inano","year":"1986","journal-title":"Steroids"},{"key":"2023011111055478900_bib3","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/ng0594-34","article-title":"Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3","volume":"7","author":"Geissler","year":"1994","journal-title":"Nat Genet"},{"key":"2023011111055478900_bib4","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1210\/jcem-32-5-604","article-title":"Familial male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect. 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