Five novel mutations in steroidogenic factor 1 (SF1,NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency
| Autor: | Heike Biebermann, Peter Heidemann, John C. Achermann, Bruno Ferraz-de-Souza, Vanessa Schröder, Lin Lin, Peter Wieacker, Birgit Köhler, Annette Grüters, Dirk Schnabel |
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| Rok vydání: | 2007 |
| Předmět: |
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 |
| Zdroj: | Human Mutation |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.20588 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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