New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression

J Clin Endocrinol Metab. 2015 Mar;100(3):994-1001. doi: 10.1210/jc.2014-2761. Epub 2014 Dec 16.


Context: Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported.

Objective: The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene.

Patients and methods: A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified.

Results: We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function.

Conclusions: In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cohort Studies
  • DNA Mutational Analysis
  • Down-Regulation / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Mutation, Missense*
  • Primary Ovarian Insufficiency / epidemiology
  • Primary Ovarian Insufficiency / genetics*
  • Stem Cell Factor / genetics*
  • Transcription Factors / genetics*
  • Young Adult


  • Homeodomain Proteins
  • NOBOX protein, human
  • Stem Cell Factor
  • Transcription Factors