title: Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a family-based genetic study and a replicate group of women with POI.
  
  
  METHODS
  The study was conducted at an academic medical center.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Thushiga
authors.initials: T
authors.lastname: Kasippillai
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Brett
authors.initials: B
authors.lastname: Thomas
authors.forename: Cornelius B
authors.initials: CB
authors.lastname: Lambalk
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Corrine K
authors.initials: CK
authors.lastname: Welt
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008594:Menopause, Premature / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C411571:EIF4ENIF1 protein, human; D029543:Nucleocytoplasmic Transport Proteins
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