DNA Replication proteins in primary microcephaly syndromes

Abstract

Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia.

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

“…The two affected individuals with the zinc binding residue variant p.(Cys158Tyr), have similar clinical features including primary microcephaly, developmental delay, typical facial characteristics, endocrine features, feeding difficulties and urogenital anomalies. These clinical features show overlap with those observed in other DNA replication disorders, such as Meier–Gorlin syndrome (MGS) and Seckel syndrome (SS) (Tingler et al 2022 ; Bellelli and Boulton 2021 ; de Munnik et al 2012 , 2015 ). Both SS and MGS are associated with variants in genes encoding pre-replication complex components (Bellelli and Boulton 2021 ; de Munnik et al 2015 ).…”

“…Because embryonic development requires rapid cell proliferation, it is particularly sensitive to genetic variants that affect DNA replication (Kalogeropoulou et al 2019 ; Nordman and Orr-Weaver 2012 ). Defects in DNA replication affect the number of cells generated during development and are, therefore, related to various human diseases, such as microcephaly and primordial dwarfism (Tingler et al 2022 ). In addition, some subunits of the MCM complex localize at the centrosome and are apparently involved in primary cilia homeostasis (Stiff et al 2013 ; Casar Tena et al 2019 ).…”

The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome

“…Noncanonical functions of some of the encoded proteins include the presence at the centrosome or cilium (reviewed in ref. [64]). There is accumulating evidence supporting ORC and MCM complexes at the centrosome [65], with this organelle serving as a possible hub for cell cycle progression interactions, such as ORC1 with cyclin E [66].…”

“…Cilia defects have been observed at a low level in MGORS patientderived cells, or when MGORS proteins are subjected to siRNA in reporter cell models [64]. Zebrafish models, using morpholinos targeting some of the MGORS proteins, show some phenotypes that overlap with those observed in zebrafish models of ciliopathies.…”

“…In these models, rescuing with a patient-informed mutant mRNA did not rescue the ciliopathic phenotypes, but wildtype mRNA also only resulted in a partial phenotypic rescue. Based on these observations, a hypothesis has been put forward that MGORS could be considered a ciliopathy [64,68,69]. Such a suggestion needs to be considered with care, for both clinical and biological reasons.…”