New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression
| Autor: | Brigitte Delemer, Jérôme Bouligand, Florence Roucher-Boulez, A.C. Hecart, Jacques Young, Cherif Beldjord, K. Azibi, Justine Bouilly, A. Mantel, Nadine Binart, Hélène Bry-Gauillard, Anne Gompel, Catherine Dodé |
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| Rok vydání: | 2014 |
| Předmět: |
Infertility
Adult medicine.medical_specialty Adolescent Endocrinology Diabetes and Metabolism Clinical Biochemistry DNA Mutational Analysis Mutation Missense Down-Regulation Context (language use) Disease Biology Primary Ovarian Insufficiency Bioinformatics medicine.disease_cause Biochemistry Cohort Studies Young Adult Endocrinology Gene Frequency Internal medicine medicine Missense mutation Humans Genetic Predisposition to Disease Allele Allele frequency Homeodomain Proteins Mutation Stem Cell Factor Biochemistry (medical) Heterozygote advantage medicine.disease HEK293 Cells Female Transcription Factors |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 100(3) |
| ISSN: | 1945-7197 |
| Popis: | Context: Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported. Objective: The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene. Patients and Methods: A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified. Results: We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function. Conclusions: In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI. |
| Databáze: | OpenAIRE |
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