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J Clin Endocrinol Metab DOI:10.1210/jc.2013-1102

Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency.

Publication TypeJournal Article
Year of Publication2013
AuthorsKasippillai, T, MacArthur, DG, Kirby, A, Thomas, B, Lambalk, CB, Daly, MJ, Welt, CK
JournalJ Clin Endocrinol Metab
Date Published2013 Sep
KeywordsAdult, Female, Genetic Predisposition to Disease, Humans, Menopause, Premature, Middle Aged, Mutation, Nucleocytoplasmic Transport Proteins, Pedigree, Primary Ovarian Insufficiency

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.


Alternate JournalJ. Clin. Endocrinol. Metab.
PubMed ID23902945
Grant ListUL1 RR025758 / RR / NCRR NIH HHS / United States
1 UL1 RR025758-01 / RR / NCRR NIH HHS / United States