Molecular Neurogenetics

Research includes:

• Identification of genes disrupted in neurodevelopmental disorders;
• Studying mechanisms of disease using (human) cell models and animal models such as fruit flies and mice;
• Epigenetic mechanisms and gene regulatory pathways;
• Development of therapeutic interventions for Kleefstra syndrome and Myotonic Dystrophy.

Discoveries include:

• Identification of many (>100) novel “disease genes” for human disorders. Prominent examples of disorders explained by his research include EEC syndrome (TP63), Robinow syndrome (ROR2), Feingold syndrome (MYCN), Kleefstra syndrome (EHMT1), Walker-Warburg syndrome (Dystroglycanopathy genes), Möbius syndrome, and many genes for Intellectual Disability (ID).
• The notion that ID genes converge to common biological pathways, which formed the basis of his inaugural lecture “Networks in the Brain”. Hans was one of the first to highlight the importance of epigenetic regulator genes in the occurrence of intellectual disability, autism, and other neurodevelopmental disorders.

We have set up a pipeline for generating and functional analysis of patient-derived neural cell lineages. Proof-of-concept was established by establishing excitatory neurons starting from blood cells and fibroblasts from patients with Kleefstra syndrome caused by mutation of the EHMT1 gene. These patient-derived neurons exhibit synaptic defects that mimic those of corresponding mouse models. In addition, culturing of these neurons on multi-electrode arrays dishes revealed gene-specific neural network anomalies. These aberrant network activities are currently used to screen chemical compound libraries to identify drugs can restore the defect, which has already revealed potential lead compounds for further inverstigation in animal models.

The Molecular Neurogenetics Unit closely collaborates with the following research groups:

• Nael Nadif Kasri, Human Genetics
• Annette Schenck, Human Genetics
• Baziel van Engelen, Neurology
• Bart van den Warrenburg, Neurology
• Rick Wansink, Cell Biology

Ongoing Grants

• IMPACT: Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy. ERARE18-144 (2019; € 1,531,026 Coordinator, budget for own group €250,000).
• Brain on a dish: development of innovative stem cell Technologies for personalized medicine in epilepsy. ZonMw Top grant (91217055); (2018; 675 k€; main applicant).
• Development of a strategy for genetic correction of repeat expansions in Myotonic Dystrophy. Prinses Beatrix Muscle Foundation (W.OR18-18). (2018; 250 k€; main applicant).
• The diagnostic utility of hiPSC-based network signatures in genetic ataxias. Radboudumc Junior researcher round 2018_DCMN (2018; 240 k€; co-application with B. van de Warrenburg).
• Pre-clinical investigation of epigenetic compounds in models for Kleefstra syndrome. GeneSpark competitive research rounds (2017; 208 k€; with N. Nadif Kasri).
• Multiscale precision therapies for neurodevelopmental disorders – MINDED. Marie Skłodowska-Curie Co-funding project (EU proposal 754490) (2017; 6 m€; coordinated by P. Decuzzi, Genua; Role co-applicant).
• Metabolic manipulation as potential treatment for the Dystroglycanopathies. Prinses Beatrix Muscle Foundation (2017; W.OR17-15). (250 k€; co-applicant with D. Lefeber and N. Voermans).
• Development of a novel cell-based strategy for correcting the neuromuscular phenotype in a myotonic dystrophy mouse model. Radboudumc Junior researcher round 2015_DCN (2015; 240 k€; co-application with B. van Engelen).

Key publications

• de Brouwer APM, Abou Jamra R, Körtel N, Soyris C, Polla DL, ..... Roignant JY#, van Bokhoven H#, Schwartz S# (2018) Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior. Am J Hum Genet. 103(6):1045-1052.
• Riazuddin S, Hussain M, Razzaq A, Iqbal Z, ….., de Brouwer AP, van Bokhoven H#, Riazuddin S# (2017) Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry 22(11):1604-1614
• Benevento M, Iacono G, Selten M, Ba W, Oudakker A, Frega M, Keller J, Mancini R, Lewerissa E, Kleefstra T, Stunnenberg HG, Zhou H, van Bokhoven H, Nadif Kasri N (2016) Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling. Neuron 91(2):341-55.
• Tomas-Roca L, Tsaalbi-Shtylik A, Jansen JG, ….. de Wind N, Padberg GW, van Bokhoven H (2015) De novo mutations in PLXND1 and REV3L cause Möbius syndrome. Nat Commun. 6:7199.
• Jae LT, Raaben M, Riemersma M, van Beusekom E, Blomen VA, Velds A, Kerkhoven RM, Carette JE, Topaloglu H, Meinecke P, Wessels MW, Lefeber DJ, Whelan SP#, van Bokhoven H#, Brummelkamp TR# (2013). Deciphering the Glycosylome of Dystroglycanopathies Using Haploid Screens for Lassa Virus Entry. Science 340:479-83.

Key awards and prizes

• Annual Award at the Dutch Society for Human Genetics (NVHG) 2018 to Britt Mossink (PhD student; role supervisor). -
• Ds. Visscher prize 2014 to M. Willemsen. Bi-annual prize for the best thesis in the area of intellectual disability. (10 k€).
• Radboud Science Award 2013. To Hans van Bokhoven and Arjan de Brouwer. For excellent research. The prestigious award has been used for developing teaching activities in the Life Sciences Area at primary schools.

EL FEB 19 update