De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

Abstract

The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

“…De novo MCM6 variants were first detected in ASD probands by Iossifov et al ( 12 ), with further reports by Takata et al ( 40 ). Subsequently, missense mutations in MCM6 were associated with neurodevelopmental phenotypes that include ASD, delayed speech development and epilepsy by Smits et al ( 72 ). MCM6 is important for primary ciliogenesis and cell proliferation ( 72, 73 ), two crucial processes during brain development.…”

“…Subsequently, missense mutations in MCM6 were associated with neurodevelopmental phenotypes that include ASD, delayed speech development and epilepsy by Smits et al ( 72 ). MCM6 is important for primary ciliogenesis and cell proliferation ( 72, 73 ), two crucial processes during brain development. Interestingly, previous studies indicate that, in the adult mouse brain, KDM5B is expressed in the neurogenic niches at the subventricular zone (SVZ) and dentate gyrus.…”