NOBOX is a strong autosomal candidate gene in Tunisian patients with primary ovarian insufficiency

Abstract

Premature ovarian insufficiency (POI) affects approximately 1% of women before the age of 40. Genetic contribution is a significant component of POI. In this context, heterozygous mutations in NOBOX, BMP15 and GDF9 have been reported. The objective of our study was to evaluate the prevalence of these genes mutations in 125 unrelated Tunisian patients diagnosed with POI. The screening of NOBOX gene revealed three missense mutations (p.Arg117Trp; p.Gly91Trp and p.Pro619Leu) in eight patients. These mutations were not found in a 200 ethnically matched women without fertility problem. The sequencing of BMP15 and GDF9 gene revealed only previously reported variants. In contrast to previous studies, the prevalence of BMP15 variations is not higher than in the control population. Conversely, 6.4% of the cases present a NOBOX mutations; this high prevalence strengthens the consideration of NOBOX gene as strong autosomal candidate for POI.

New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family

“…This variant is reported both in the Exome Sequencing Project and the ExAC database (minor allele frequency, 7.7%). In addition, we have found it in our cohort of 125 Tunisian patients with POI, in 3 patients in the heterozygous state and 1 patient in the homozygous state (14). Thus, despite having been described as responsible for an important part of the high prevalence of NOBOX variants in POI, this variant does not seem to have a major role in our family with POI related to MCM8.…”

“…A final elongation step of 72 C for 5 seconds was added in each case. Rare GDF9 and NOBOX variants were validated as previously described (14).…”

Genetics of primary ovarian insufficiency

“…Follicles are then replaced by fibrous tissue in female knockout mice in a manner similar to OD in women . Further corroborating the importance of NOBOX activity for folliculogenesis, heterozygous NOBOX mutations have been consistently reported in women with sporadic POI of African and Caucasian origin at a prevalence of approximately 6% (POF5, OMIM #611548) , suggesting to consider NOBOX as the first autosomal candidate gene involved in POI . Vice versa, mutations in the homeobox domain of NOBOX seem not to be common explanations for POI in Asian women .…”

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

“…Women with nonsyndromic POI showed heterozygous mutations not only in BMP15 or GDF9 but also in other key genes of ovarian function, such as NOBOX, FOXL2, SOHLH1, FIGLA, GALT, STAG3, HFM1, SYCE1, MCM8, MCM9, SCM1β, REC8, LHX8, and many more, involved in cell functions such as regulation of transcription, meiosis, and DNA repair (Bouali et al, 2016; Bouilly et al, 2016; Qin et al, 2015). A recent study on whole-exome sequencing of Chinese POI patients showed a novel homozygous truncating variant in the NOBOX gene (chr7:144098161delC) that impaired severely the transcriptional activation of the GDF9 gene in functional analyses, suggesting that a loss-of-function effect on NOBOX transcriptional activity could be associated with POI via reduced GDF9 (Li et al, 2017).…”