A non‐sense MCM9 mutation in a familial case of primary ovarian insufficiency

Abstract

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/-mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

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

“…Furthermore, the Mcm9 (-/-) females are sterile because ovaries are devoid of oocytes (19). In addition, mutations of theMCM9 gene have been recently described in patients with POI (10,11). Taken together, these results show the importance of the MCM8/MCM9 pathway in the spectrum of ovarian functions.…”

“…It is known that genetic factors are a significant component of ovarian insufficiency, nearly a third of cases being familial (16). Furthermore, recent whole-exome sequencing studies provide evidence for the possible contribution of several genes to POI pathogenesis (7)(8)(9)(10)(11). In the present study, we examined a highly consanguineous Tunisian family with several affected siblings born to parents who were second-degree cousins.…”

“…The emergence of other strategies has generated more reliable results and has helped to identify new genes involved in the etiology of POI. For instance, genome-wide association studies and whole-exome sequencing have revealed novel genomic regions that are associated with ovarian insufficiency and age of menopause such as Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex components 8 and 9 (MCM8, MCM9), and adenosine triphosphate (ATP)-dependent DNA helicase homologue (HFM1) genes (7)(8)(9)(10)(11). These genes are involved in DNA replication and repair during meiosis, and chromosome stability (8,9,12).…”

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

“…Another MCM9 heterozygous carrier (c.911A>G; p.N304S) also harbored a predicted neutral (REVEL) variant in MCM8 (c.1561G>A; p.D521N) (Desai et al, ). That same year, a homozygous nonsense mutation (c.1483G>T; p.E495*) was identified in two POI‐affected sisters from a consanguineous Middle Eastern family of Arab origin (Fauchereau et al, ). A detailed description of the reported MCM9 mutation carriers is shown in Table .…”

Pathogenic germline MCM9 variants are rare in Australian Lynch-like syndrome patients

“…[13][14][15]. The proband homozygous for c.672_673delGGinsC also developed early-onset CRC and mixed polyposis, and three heterozygous relatives had an attenuated phenotype of late CRC or few polyps [15], indicating a potential role for perturbed MCM9 function contributing to the development of CRC.…”