Five novel mutations in steroidogenic factor 1 (SF1,NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency
| العنوان: | Five novel mutations in steroidogenic factor 1 (SF1,NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency |
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| المؤلفون: | Heike Biebermann, Peter Heidemann, John C. Achermann, Bruno Ferraz-de-Souza, Vanessa Schröder, Lin Lin, Peter Wieacker, Birgit Köhler, Annette Grüters, Dirk Schnabel |
| المصدر: | Human Mutation |
| بيانات النشر: | Hindawi Limited, 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Adult, Steroidogenic factor 1, endocrine system, medicine.medical_specialty, Adolescent, Nonsense mutation, NR5A1, Gonadal dysgenesis, Biology, Steroidogenic Factor 1, medicine.disease_cause, Frameshift mutation, Cohort Studies, Internal medicine, Adrenal Glands, Genetics, medicine, Adrenal insufficiency, Humans, Missense mutation, nuclear receptor, Child, steroidogenic factor-1, Genetics (clinical), Gonadal Dysgenesis, 46,XY, Mutation, gonadal dysgenesis, disorders of sex development (DSD), medicine.disease, SF1, Endocrinology, male pseudohermaphroditism, Child, Preschool, Female, Haploinsufficiency, Adrenal Insufficiency, Research Article |
| الوصف: | Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Müllerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]+[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Müllerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans. |
| تدمد: | 1098-1004 1059-7794 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::143227e274ab3ab3c2d7ecfdb2890131Test https://doi.org/10.1002/humu.20588Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....143227e274ab3ab3c2d7ecfdb2890131 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10981004 10597794 |
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