OR44-3 A Mutation in eIF4ENIF1 Causes Primary Ovarian Insufficiency

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR44-Female Reproductive Endocrinology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:45 AM
Room 256 (Moscone Center)
Thushiga Kasippillai*1, Daniel G. McArthur2, Andrew Kirby2, Brett Thomas2, Mark Daly2 and Corrine K. Welt2
1VU University Medical Center, Amsterdam, Netherlands, 2Massachusetts General Hospital, Boston, MA
Background:Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion and consequent elevation of FSH levels before age 40 years. We identified a family in which nine women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance.

Methods: Family based whole exome sequencing was performed in 6 affected women and the father of the proband. We searched for a high impact, deleterious variant shared among the 6 affected women but absent in the father and 6,503 European and African American subjects in the Exome Variant Server (1), 1,092 subjects of differing ethnicity in the 1000 genomes project (2) and 870 European ATGU controls (3). The genotypes of interest were confirmed and genotypes of 1 additional affected woman, an obligate male carrier and 6 unaffected family members were determined using Sanger sequencing. The genes of interest were also sequenced in 38 unrelated women with POI. In addition, mRNA was isolated from the proband’s affected mother, cDNA was reverse transcribed after DNase treatment and PCR was performed.

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<0.05). The cDNA reverse transcribed from the affected mother's mRNA did not contain a transcript with the stop codon. There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI.

Conclusion: Data demonstrate that a stop codon in eIF4ENIF1 is associated with dominantly inherited POI through haploinsufficiency. Importantly, the homologous Drosophila protein Cup acts as a translational repressor during germ cell development and mutations result in a dominant disruption of meiotic chromosome segregation in oocytes. Further, previous studies demonstrate a role for the translation initiation factor eIF2B genes in ovarian insufficiency associated with white matter disease. Therefore, these results highlight the importance of translation initiation factors and their regulators in ovarian function.

(1) NHLBI GO Exome Sequencing Project (ESP). 2012 URL: http://evs gs washington edu/EVS/ Seattle, WA:accessed October, 2012. (2) Abecasis GR, Auton A, Brooks LD, et al. 2012 An integrated map of genetic variation from 1,092 human genomes. Nature 491:56-65. (3) Neale BM, Kou Y, Liu L, et al. 2012 Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242-245.

Disclosure: CKW: , Up To Date. Nothing to Disclose: TK, DGM, AK, BT, MD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by the Harvard Clinical and Translational Science Center Grant Number 1 UL1 RR025758-01.