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J Clin Endocrinol Metab. 2013 Sep;98(9):E1534-9. doi: 10.1210/jc.2013-1102. Epub 2013 Jul 31.

Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency.

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1
Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

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 < .05). There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI.

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.

PMID:
23902945
PMCID:
PMC5393467
DOI:
10.1210/jc.2013-1102
[Indexed for MEDLINE]
Free PMC Article
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