Research group Neurogenetics

Malformations of cortical development: identification of novel genes and their function

Coordinator: Prof. A. Jansen

Collaborators: Prof. K. Stouffs, Prof. S. Seneca, Dr. A. Gheldof

Predoctoral students: I. Tanyalcin, L. Vandervore

Past collaborators: Prof. W. Lissens

The development of the cerebral cortex is extremely complex but can nevertheless be divided into different, partly overlapping stages. Interference with one or more of these processes by genetic or external factors may result in malformations of cortical development (MCD). The most prevalent MCDs include lissencephaly/subcortical band heterotopia, polymicrogyria, periventricular heterotopia and focal cortical dysplasia. MCDs are an important cause of mental and motor impairment, severe epilepsy, learning disorders, and autism. Patients require a lifelong multidisciplinary follow-up and treatment is restricted to symptom relief. Most MCD have a genetic etiology but there is extensive heterogeneity both with respect to genotypes and phenotypes. For the large majority of patients with MCDs, the exact etiology of their disorder is still unknown, leaving a considerable number of families not having access to counseling or prenatal diagnosis in order to prevent recurrence.

The different projects aim at the further identification of genes involved in the regulation of neuronal migration and the study of the functional consequences of mutations in these genes by combining patient-driven molecular genetic studies and comparative genetic research in zebrafish models. This will result in mapping of major pathways involved in cortical development and function.

Part of the project is performed in collaboration with the research groups of Prof. Peter De Witte (Laboratory for Pharmaceutical Biology, KUL - zebrafish models).

Publications

Jansen AC, Robitaille Y, Honavar M, Mullatti N, Leventer RJ, Andermann E, Andermann F, Squier W. The histopathology of polymicrogyria: a series of 71 brain autopsy studies. Dev Med Child Neurol. 2015 Jul 14. doi: 10.1111/dmcn.12840.

Squier W, Jansen A. Polymicrogyria: pathology, fetal origins and mechanisms. Acta Neuropathol Commun. 2014 Jul 22;2(1):80

De Bruyn C, Vanderhasselt T, Tanyal¨in I, Keymolen K, Van Rompaey KL, De Meirleir L, Jansen AC. Thin genu of the corpus callosum points to mutation in FOXG1 in a child with acquired microcephaly, trigonocephaly, and intellectual developmental disorder: A case report and review of literature. Eur J Paediatr Neurol. 2014 May;18(3):420-6

Tanyal¨in I, Verhelst H, Halley DJJ, Vanderhasselt T, Villard L, Goizet C, Lissens W, Mancini GM, Jansen AC. Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review. Eur J Paediatr Neurol, Eur J Paediatr Neurol. 2013 Nov;17(6):666-70

Amrom D, Tanyal¨in I, Verhelst H, Deconinck N, Brouhard GJ, Dˇcarie JC, Vanderhasselt T, Das S, Hamdan F, Lissens W, Michaud J, Jansen AC. Polymicrogyria with dysmorphic basal ganglia? Think tubulin! Clin Genet. 2013 Mar 15. doi: 10.1111/cge.12141

Handley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C, Bem D, Carpanini SM, Borck G, Martorell L, Izzi C, Faravelli F, Accorsi P, Pinelli L, Basel-Vanagaite L, Peretz G, Abdel-Salam GM, Zaki MS, Jansen A, Mowat D, Glass I, Stewart H, Mancini G, Lederer D, Roscioli T, Giuliano F, Plomp AS, Rolfs A, Graham JM, Seemanova E, Jackson IJ, Maher ER, Aligianis IA. Mutation Spectrum in RAB3GAP1, RAB3GAP2 and RAB18 and Genotype-Phenotype Correlations in Warburg Micro syndrome and Martsolf Syndrome. Hum Mutat. 2013;34(5):686-96

Jansen AC, Oostra A, Desprechins B, De Vlaeminck Y, Verhelst H, Regal L, Verloo P, Bockaert N, Keymolen K, Seneca S, De Meirleir L, Lissens W. TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria. Neurology 2011;76:988-992

Squier W and Jansen A. Abnormal development of the human cerebral cortex. J Anat. 2010;217:312-23

Leventer RJ, Jansen A, Pilz DT, Stoodley N, Marini C, Dubeau F, Malone J, Mitchell LA, Mandelstam S, Scheffer IE, Berkovic SF, Andermann E, Andermann F, Guerrini R, Dobyns WB. Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain 2010 May;133(Pt 5):1415-27

Jansen AC. Cognitive deficits and developmental language disorders in patients with malformations of cortical development. Epilepsia 2010 Feb;51 Suppl 1:70-1

Wieck G, Leventer R, Squier W, Jansen A, Andermann E, Dubeau F, Ramazzotti A, Guerrini R, Dobyns W. Periventricular nodular heterotopia with overlying polymicrogyria. Brain 2005;128:2811-2821

Jansen A and Andermann E. Genetics of the polymicrogyria syndromes. J Med Genet, 2005;42:369-78

Kobayashi E, Bagshaw AP, Jansen A, Andermann F, Andermann E, Gotman J, Dubeau F. Intrinsic epileptogenicity in polymicrogyric cortex suggested by EEG-fMRI BOLD responses. Neurology, 2005;64:1263-6

Jansen A, Leonard G, Festen J, Bastos AC, Tampieri D, Watkins K, Andermann F, and Andermann E. Cognitive functioning in bilateral perisylvian polymicrogyria. Epilepsy and Behavior, 2005;6:393-404

Sheen V, Jansen A, Ravenscroft R, Ganesh V, Underwood T, Wiley J, Leventer R, Vaid R, Hutchins G, Menasha J, Willner J, Rimmer W, Geng Y, Gripp K, Nicholson L, Berry-Kravis E, Bodell A, Apse K, Hill RS, Dubeau F, Andermann F, Barkovich J, Andermann E, Yao Y, Thomas P, Guerrini R, Walsh C. Ehlers-Danlos variant of periventricular heterotopia. Neurology 2005;64:254-62

Team

Sara Seneca, PI

Katrien Stouffs, PI

Alexander Gheldof, PI

Anna Jansen, PI

Deborah Vandermaelen, Lab technician

Ibrahim Tanyalcin, PhD student. Ibrahim Tanyalcin completed his undergraduate degree at Bogazi¨i University in 2009. He obtained a master's degree in Cell and Gene Therapy from VUB with great distinction. He subsequently pursued a PhD in Malformations of Cortical Development under the guidance of Prof. Anna Jansen, Prof. Katrien Stouffs and Prof. Willy Lissens. His main focus was the identification of novel genes involved in cerebral cortical development and the study of their function. He worked in variant prioritization, variant effect prediction, experimental validation of variants detected by exome sequencing and data visualization.

 

Laura Vandervore, PhD student. Laura Vandervore studied Pharmaceutical Sciences at the VUB and graduated with great distinction in 2015. For her master thesis she studied potential biomarkers for real time pancreatic beta cell dead in type 1 Diabetes mellitus. She joined the REGE team in October 2015 after obtaining a scholarship from the Marguerite-Marie Delacroix foundation. Her project will focus on the functional analysis of (new) genes selected from whole exome sequencing studies in patients with malformations of cortical development.

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