CONTEXT: Primary ovarian insufficiency (POI) is a disorder affecting approximately 1% of women under the age of 40 years. NR5A1 (SF-1) mutations have been recently reported in association with POI. OBJECTIVE: Our objective was to evaluate the frequency and functional impact of NR5A1 variants in POI. PATIENTS AND METHODS: One hundred eighty patients diagnosed with idiopathic POI were screened for NR5A1 mutations and functional analysis was performed for the identified variants. The DNA-binding capacity of the variants was evaluated by means of EMSA, while their transcriptional activity was assessed using luciferase reporter assays. RESULTS: Sequencing the NR5A1 gene revealed 4 missense variants in 3 patients. These patients were aged 20, 25, and 33 years at diagnosis and presented with secondary amenorrhea. None of them presented a syndromic form, although 2 had a familial history of POI. The functional analysis carried out for these missense variants showed no significant difference in DNA binding capacity or in transcriptional activity compared to wild-type NR5A1. CONCLUSIONS: Our study in a large cohort of patients with POI showed the prevalence of NR5A1 mutations to be low (1.6%, upper 95% confidence interval 3.5%). Moreover, no functional impact was observed. Overall, in contrast with the initial report, our results exclude NR5A1 mutations as a major genetic cause of POI.
CONTEXT: Primary ovarian insufficiency (POI) is a disorder affecting approximately 1% of women under the age of 40 years. NR5A1 (SF-1) mutations have been recently reported in association with POI. OBJECTIVE: Our objective was to evaluate the frequency and functional impact of NR5A1 variants in POI. PATIENTS AND METHODS: One hundred eighty patients diagnosed with idiopathic POI were screened for NR5A1 mutations and functional analysis was performed for the identified variants. The DNA-binding capacity of the variants was evaluated by means of EMSA, while their transcriptional activity was assessed using luciferase reporter assays. RESULTS: Sequencing the NR5A1 gene revealed 4 missense variants in 3 patients. These patients were aged 20, 25, and 33 years at diagnosis and presented with secondary amenorrhea. None of them presented a syndromic form, although 2 had a familial history of POI. The functional analysis carried out for these missense variants showed no significant difference in DNA binding capacity or in transcriptional activity compared to wild-type NR5A1. CONCLUSIONS: Our study in a large cohort of patients with POI showed the prevalence of NR5A1 mutations to be low (1.6%, upper 95% confidence interval 3.5%). Moreover, no functional impact was observed. Overall, in contrast with the initial report, our results exclude NR5A1 mutations as a major genetic cause of POI.
Authors: Jenifer P Suntharalingham; Federica Buonocore; Andrew J Duncan; John C Achermann Journal: Best Pract Res Clin Endocrinol Metab Date: 2015-07-14 Impact factor: 4.690
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Authors: Ingrid M Knarston; Gorjana Robevska; Jocelyn A van den Bergen; Stefanie Eggers; Brittany Croft; Jason Yates; Remko Hersmus; Leendert H J Looijenga; Fergus J Cameron; Klaus Monhike; Katie L Ayers; Andrew H Sinclair Journal: Hum Mutat Date: 2018-11-30 Impact factor: 4.878
Authors: Jocelyn A van den Bergen; Gorjana Robevska; Stefanie Eggers; Stefan Riedl; Sonia R Grover; Philip B Bergman; Chris Kimber; Ashish Jiwane; Sophy Khan; Csilla Krausz; Jamal Raza; Irum Atta; Susan R Davis; Makato Ono; Vincent Harley; Sultana M H Faradz; Andrew H Sinclair; Katie L Ayers Journal: Mol Genet Genomic Med Date: 2020-01-21 Impact factor: 2.183