|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|
|Date Published||2013 Sep|
|Keywords||Adult, 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 Journal||J. Clin. Endocrinol. Metab.|
|Grant List||UL1 RR025758 / RR / NCRR NIH HHS / United States |
1 UL1 RR025758-01 / RR / NCRR NIH HHS / United States