The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency

Abstract

Infertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (<30 years) at the time of the study. In the male patient the homozygous MCM9 variant led to normal pubertal development and hormonal levels but caused a Sertoli-cell-only syndrome with non-obstructive azoospermia. In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated.

A Human Homozygous HELQ Missense Variant Does Not Cause Premature Ovarian Insufficiency in a Mouse Model

“…Although the female Mcm9 knock-out mice were sterile due to a lack of oocytes, male knock-outs were fertile with fewer germ cells compared to their Wt counterparts [ 94 , 95 ]. By contrast, both male and female humans are infertile if the MCM9 gene is disrupted [ 30 , 96 ]. These studies highlight some of the limitations when using meiosis and DNA repair genes in mouse models when trying to recapitulate gonadal development processes.…”

Mode of inheritance needs to be accounted for in interpreting genotype-phenotype links in monogenic disorders

“…An example of a well-established autosomal-recessive (AR) gene is FSHR , the first discovered POI locus 8 . Other examples of recessive POI genes with monoallelic findings by Ke et al are SPIDR 9,10 , MSH4 11 , EIF2B2 12 , and MCM9 13 . Conducted family-based studies have identified no POI phenotype in the heterozygous mothers (carriers of damaging variants) of affected homozygous daughters.…”

“…The available data for 18 genes (in this commentary referred as 'Unclear') was insufficient to conclusively determine their specific inheritance mode. , and MCM9 13 . Conducted family-based studies have identified no POI phenotype in the heterozygous mothers (carriers of damaging variants) of affected homozygous daughters.…”