New NR5A1 mutations and phenotypic variations of gonadal dysgenesis
| Autor: | Lutz Wünsch, Karl Otfried Schwab, Christoph Thorns, Olaf Hiort, Benedikt Reiz, Paul-Martin Holterhus, Gerhard Binder, Isabel Mönig, Ralf Lünstedt, Ralf Werner, Alexandra Krause |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Hydrocortisone Anorchia Gonadal dysgenesis lcsh:Medicine Electrophoretic Mobility Shift Assay Restriction Fragment Mapping Gonadal Dysgenesis Steroidogenic Factor 1 medicine.disease_cause Biochemistry Medicine and Health Sciences Morphogenesis Missense mutation Testosterone Lipid Hormones Disorders of sex development Child Frameshift Mutation lcsh:Science Pharmacologic-based diagnostics Exome sequencing Genetics Hypospadias Mutation Multidisciplinary Phenotype Androgens Female Anatomy Genital Anatomy Traditional ACTH stimulation test Research Article medicine.medical_specialty endocrine system Adolescent Biology Research and Analysis Methods Frameshift mutation 03 medical and health sciences Internal medicine Congenital Disorders medicine Humans Birth Defects Gonads Molecular Biology Techniques Molecular Biology Pharmacology Steroid Hormones Gene Mapping lcsh:R Reproductive System Biology and Life Sciences medicine.disease Hormones 030104 developmental biology Endocrinology lcsh:Q T-Box Domain Proteins Follow-Up Studies HeLa Cells Developmental Biology |
| Zdroj: | PLoS ONE, Vol 12, Iss 5, p e0176720 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling’s family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations. |
| Databáze: | OpenAIRE |
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