MC M9, a protein involved in DNA replication and repair, has been the subject of numerous research articles due to its role in a variety of biological processes.
In particular, it is known to form a complex structure with MCM8 and participate in DNA mismatch repair (MMR) and homologous recombination.
Mutations in MCM9 can cause ovarian failure and, in some cases, make individuals prone to early colorectal cancer.
Overview: MC M9 EV 2025
Delay in puberty in girls is often related to late maturation, but is sometimes the first sign of premature ovarian insufficiency (POI).
POI is a condition that affects ovarian function and fertility, and in most cases the cause is unknown.
Recently, genetic factors have been identified in 20–25% of women with POI, including genes controlling various aspects of ovarian development and maintenance.
We report a case of delayed puberty due to POI in an adolescent from a non-consanguineous family who had two variants in the MCM9 gene.
MCM9 is essential for DNA replication and repair, and its malfunction can lead to chromosomal instability and ovarian failure.
Our case highlights the importance of targeted gene panel analysis, particularly in POI patients with negative autoimmunity screening and evidence of ovarian or uterine digenesis on pelvic imaging.
- Delayed puberty in girls is often self-limited, but it can also indicate underlying conditions with lifelong implications, such as premature ovarian insufficiency.
- Patients with POI, negative autoimmune screening, a normal karyotype, and no FMR permutation should undergo further genetic testing, preferably via a targeted gene panel.
- Compound heterozygous variants in MCM9 can cause POI, presenting with delayed puberty and primary amenorrhea in girls with no consanguineous family.
Background
Delayed puberty in girls is defined as the absence of breast development by age 13 or the absence of menstruation by age 15.
Although delayed puberty is often self-limiting and only a sign of late sexual maturation, it can sometimes be the first sign of an underlying condition with lifelong implications, such as premature ovarian insufficiency (POI).
POI is defined by amenorrhea for more than 4 months before the age of 40 years, excluding pregnancy, and elevated serum follicle-stimulating hormone levels >25 U/L, confirmed by at least two blood samples >4 weeks apart.
The rate of follicular atresia in POI can be influenced by various factors such as iatrogenic interventions, autoimmune disease, metabolic disease, infections, and genetic defects involved in folliculogenesis or steroid hormone synthesis and response.
A genetic predisposition in idiopathic cases is suggested by the high incidence of familial aggregation, which may account for up to 20–25% of cases.
POI comprises a variety of phenotypes, including ovarian dysgenesis, primary amenorrhea (PA), secondary amenorrhea (SA), premature ovarian failure, and premature menopause.
Given the heterogeneous genetic basis of POI, which involves pathogenic variants in multiple genes, molecular genetic analysis of a gene panel is important in the diagnostic workup.
Genome-wide association studies have identified gene loci associated with meiosis or DNA repair pathways,
such as minichromosome maintenance (MCM8) and minichromosome maintenance 9 (MCM9), which may play a role in ovarian aging (Several studies reported homozygous and compound heterozygous variants in MCM8 and MCM9 genes in patients with POI,
displaying phenotypic variations that range from PA to SA, and exhibiting short to normal stature.
Homozygous variants are hitherto exclusively found in consanguineous families of Arab, Turkish, or Jewish origin.
Structural Studies
- Heterohexameric ring: MCM8 and MCM9 have been proposed to form a heterohexameric ring with a central channel for DNA.
- DNA Binding/Unwinding: Research suggests that MCM8/9 can bind to and unwind DNA, possibly through protrusion into the central channel of the OB domain.
- Conformational Changes: Structural dynamic analysis reveals that the MCM8/9 complex undergoes structural changes during DNA unwinding, particularly in the N-tier and C-tier rings.Â