Genomic Variants and Variations in Malformations of Cortical Development

Abstract

Malformations of cortical development (MCD) are a common cause of neurodevelopmental delay and epilepsy and are caused by disruptions in the normal development of the cerebral cortex. Advances in genetic tools have expanded our understanding of the genetics of these malformations over the past few years, with a number of new causative genes identified in patients with MCD. In addition, there has been a vast expansion in the phenotypic characterization of the known genes, with a wide range as well as severity of malformations being reported. There is increasing evidence of role of de novo mutations, including those occurring post fertilization, in MCD. These “somatic” mutations may not be detectable by traditional methods of genetic testing performed on blood DNA. Identification of the genetic etiology can help in guiding families in future pregnancies. Recent work has highlighted how elucidation of key molecular pathway can also allow for targeted therapeutic interventions.

oRGs and mitotic somal translocation — a role in development and disease

“…Genes shown to interact with this pathway have been linked to several types of cortical malformations, including forms of primary microcephaly ( ASPM ), periventricular nodular heterotopia ( ARFGEF2, FLNA, FMR1 ), cobblestone malformations ( GPR56 ), and lissencephaly ( RELN ) [2 •• ,37]. Neuronal migration was first hypothesized to be the primary target of many of these mutations because NMII plays an important role in neuronal migration [38], and the motility of neural stem cells such as oRG cells was not previously appreciated.…”

Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

“…Proper development of the nervous system is critical for its function, and deficits in neural development have been implicated in many brain disorders, such as microcephaly, autistic spectrum disorders, and schizophrenia (Jamuar and Walsh, 2015; Taverna et al, 2014). In the embryonic mouse cortex, radial glia cells (RGCs) function as neural stem cells, sequentially giving rise to neurons residing in different cortical layers and then switching to glial production before their depletion during early postnatal stages (Taverna et al, 2014).…”

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

“…The common link between these processes is insufficient proliferation, specifically in neural stem or progenitor cells. Reduced proliferation may be caused by some combination of inappropriate cell death and loss of proliferative potential through premature differentiation or senescence [2] . Heritable microcephaly syndromes result from mutations in genes that are specifically required by neural stem or progenitor cells to maintain their survival and proliferation.…”