MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency

Abstract

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication.

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…Importantly, premature senescence was shown to impair adipogenesis in human pluripotent stem cells lacking either WRN or BLM helicases ( 108 ). Several other DNA replication/repair-associated lipodystrophies have been described ( 7 , 78 , 109 , 110 ), frequently associated with short stature, hypogonadism, and trophic skin disorders, among other progeroid signs.…”

DNA Replication proteins in primary microcephaly syndromes

“…Three members of the MCM complex have been identified as candidate genes for MGORS and hence primary microcephaly (Knapp et al., 2021; Vetro et al., 2017). In addition to their role in origin licensing and DNA unwinding, MCM proteins can be detected at the centrosome and dysfunction of MCMs impacts on centrosomal and/or ciliary structure and function (Casar Tena et al., 2019; Ferguson et al., 2010; Stuermer et al., 2007).…”

Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome

“…Other phenotypes associated with MGS include respiratory and gastrointestinal problems, skeletal and genitourinary anomalies, and facial characteristics such as down-slanting palpebral fissures and full lips (20). Of interest here, pathogenic variants associated with MGS have been identified in the genes encoding subunits of the origin recognition complex ORC1, ORC4, and ORC6 (21); components of the CMG complex MCM3 (22), MCM5 (23), MCM7 (22), CDC45 (24)(25)(26)(27), and GINS2 (28); factors involved in the assembly of the CMG complex CDT1, CDC6 (21),and GMNN (29); and DONSON, a protein that promotes replication fork stability (30). Additionally, pathogenic variants in genes encoding CMG components MCM4 (31,32), MCM7 (22), CDC45 (26), and GINS1 (33,34) have been associated with other forms of primordial dwarfism.…”