Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Kasippillai, T, MacArthur, DG, Kirby, A, Thomas, B, Lambalk, CB, Daly, MJ, Welt, CK |
Journal | J Clin Endocrinol Metab |
Volume | 98 |
Issue | 9 |
Pages | E1534-9 |
Date Published | 2013 Sep |
ISSN | 1945-7197 |
Keywords | Adult, Female, Genetic Predisposition to Disease, Humans, Menopause, Premature, Middle Aged, Mutation, Nucleocytoplasmic Transport Proteins, Pedigree, Primary Ovarian Insufficiency |
Abstract | CONTEXT: Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion with a consequent elevation of FSH levels before age 40 years. We identified a family in which 9 women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance. DESIGN: This was a family-based genetic study and a replicate group of women with POI. SETTING: The study was conducted at an academic medical center. PATIENTS: Seven affected women and an obligate carrier and 7 unaffected family members were genotyped. The genes of interest were also sequenced in 38 unrelated women with POI. INTERVENTION: The DNA from 7 family members was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of additional family members and unrelated women with POI were determined using Sanger sequencing. MAIN OUTCOME MEASURE: A high-impact, deleterious variant that segregated appropriately with POI in the family was required. RESULTS: A heterozygous stop codon (Ser429X) was identified in the eukaryotic translation initiation factor 4E nuclear import factor 1 (eIF4ENIF1) in the proband and all affected women but not in the unaffected family members. The chance that such a high-impact, deleterious variant would segregate appropriately among the affected and unaffected relatives by chance is very low (P CONCLUSION: Data demonstrate a new gene associated with dominantly inherited POI. These results highlight the importance of translation initiation factors and their regulators in ovarian function. |
URL | http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=23902945 |
DOI | 10.1210/jc.2013-1102 |
Pubmed | |
Alternate Journal | J. Clin. Endocrinol. Metab. |
PubMed ID | 23902945 |
Grant List | UL1 RR025758 / RR / NCRR NIH HHS / United States 1 UL1 RR025758-01 / RR / NCRR NIH HHS / United States |
J Clin Endocrinol Metab DOI:10.1210/jc.2013-1102
Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency.
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