Mental Retardation: Elucidation of the Molecular Basis of Cognitive Disorders.

Investigators: Hans van Bokhoven (Group Leader), Arjan de Brouwer (Subtheme leader), Jamie Kramer (Postdoc, Drosophila Group), Zafar Iqbal (PhD student), Monique Balemans (PhD student), Astrid Oudakker (Technician) and Gemma Carvill (visiting PhD student)

Summary:

The general Aim of this research is to resolve the molecular basis of mental retardation (MR). The identification of MR genes helps to unravel pathways and mechanisms in neural signaling, which are crucial for normal cognitive functions and whose disruption lead to mental retardation. We are an enthusiastic multidisciplinary group intensively collaborating in this highly translational research theme. We have strong ties to the clinic, where our colleagues are seeing MR patients at a regular basis. As a consequence, we have access to material from a large group of clinically well-characterized patients with X-linked and autosomal forms of MR, with or without associated phenotypic features. We use state-of-the art genetics and genomics strategies to elucidate the causative genetic defect: positional cloning, homozygosity mapping and the detection of genomic copy number variations by SNP microarray analysis. This work is conducted within a Consortium of internationally renowned groups (www.euromrx.com). We have found that the products of the mutated genes are often interacting with one another in the same protein complexes and cellular pathways. Examples include RhoGTPase signaling and chromatin remodeling. To gain further insight into these pathways, we conduct a variety of functional genomics approaches. A major emphasis is placed on epigenetic processes that are disrupted by MR gene mutations. In particular, the EHMT1 gene, encoding a euchromatic histone methyltransferase is studied in Drosophila models (LINK to DROSOPHILA models), mouse models and cellular systems. The close interaction between scientist from various disciplines provides a highly stimulating research environment. The generated new insights into the molecular genetic pathways of MR will be readily used to improve diagnostic and clinical management of patients. Ultimately, these new insights into MR pathology may provide a handle for the development of new strategies for therapeutic interventions.

Selected Publications:

de Brouwer AP, Williams KL, Duley J, van Kuilenburg AB, Nabuurs S, Egmont-Petersen M, Lugtenberg D, Zoetekouw L, Banning MJ, Roeffen M, Hamel BC, Weaving L, Ouvrier RA, Donald JA, Wevers RA, Christodoulou J, van Bokhoven H (2007) Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet 81, 507-518. PubMed

Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H (2006) Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome. Am J Hum Genet 79, 370-377. PubMed

Lugtenberg D, Yntema HG, Banning MJ, Oudakker AR, Firth HV, Willatt L, Raynaud M, Kleefstra T, Fryns JP, Ropers HH, Chelly J, Moraine C, Gecz J, Reeuwijk JV, Nabuurs SB, de Vries BB, Hamel BC, de Brouwer AP, van Bokhoven H (2006) ZNF674: A New Kruppel-Associated Box-Containing Zinc-Finger Gene Involved in Nonsyndromic X-Linked Mental Retardation. Am J Hum Genet. 78, 265-278. PubMed

Kutsche K., Yntema H., Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BCJ, van Bokhoven H and Gal A (2000) Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nature Genetics 26, 247-250. PubMed