Cortical malformation disorders

The development of the brain cortex is a complex process, which is strictly regulated in time and space. Rare genetic mutations that affect this process can have profound consequences for the intellectual development, motor skills such as speech and walking, and behaviour, leading to a broad range of intellectual disability, autism, cerebral palsy and seizures. We specifically focus on malformations of the cerebral cortex, classified on radiological (MRI) pattern, such as lissencephaly, nodular heterotopia, polymicrogyria, microcephaly, megalencephaly, schizencephaly and porencephaly. All of these are rare, and very little is known about the cause and disease mechanisms. We aim at discovering new genes and disease mechanisms.

The research on cortical malformations is carried out at the Dept. of Clinical Genetics (Mancini lab) and primarily aimed at the identification of the genes that cause cortical malformation. Thereto, stored material of undiagnosed patients is used to test novel candidate genes with WES/WGS, RNAseq, and functional biochemical tests at cell and stem cell biological level. The focus lies on specific mechanisms involved in brain development, such as regulation of cell-cell interaction (e.g. formation and function of primary cilia and cell migration), cell proliferation (regulation of mitosis) and regulation of cell death (apoptosis). We not only use cellular models but also Zebrafish to investigate the role of these genes. Broad national and international collaborations allow confirmation and validation in additional individuals.

Currently, we have discovered brain malformations caused by mutations in the following genes: AP4M1, IER3IP1, RTTN, COL4A2, USP18, MOCS3, INTS1, INTS8, MACF1, CARS, SMPD4, TMX2. The Mancini group has also collaborated to the characterization of brain malformations and of human mutations in the following genes: ACTB, PIK3CA, AKT3, CCND2, SCN3A, APC2, EML1, ISPD, CSTB, PNKP, ZIC1.

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Dobyns WB, et.al. (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet. Pubmed

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Mancini, G.M.S. et al. (2004) Hereditary porencephaly: clinical and MRI findings in two Dutch families. Eur J Paediatr Neurol 8, 45–54. Pubmed