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A report of two novel NR 5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression
Author(s) -
Suwanai Ayuko S.,
Ishii Tomohiro,
Haruna Hidenori,
Yamataka Atsuyuki,
Narumi Satoshi,
Fukuzawa Ryuji,
Ogata Tsutomu,
Hasegawa Tomonobu
Publication year - 2013
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12054
Subject(s) - depression (economics) , anxiety , mutation , medicine , adrenal insufficiency , disorders of sex development , phenotype , steroidogenic factor 1 , genetics , psychiatry , biology , endocrinology , psychology , gene , nuclear receptor , transcription factor , economics , macroeconomics
Summary Objective NR 5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus–pituitary–steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development ( DSD ) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus‐specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms. Design and methods We screened for NR 5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR ‐based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR 5A1 s were studied in silico and in vitro , including three‐dimensional (3D) mutation models, subcellular NR 5A1 protein localization and transactivation assays. Results We found 2 (46,XY) patients with NR 5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR 5A1 localization and impaired transcriptional activation without dominant‐negative effects in both mutations. Conclusions We found 2 (46,XX) NR 5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR 5A1 mutations.