Developmental Disorders: Elucidating the Molecular Basis of Human Syndromes with Multiple Congenital Anomalies.

Investigators: Hans van Bokhoven (Group Leader), Jo HuiqingZhou (Subtheme leader), Tony Roscioli (Postdoc), Tuula Rinne (PhD student), Ellen van Beusekom (Technician), Emine Bolat (Technician) and Ronald Rieder (Technician)

Summary:

The general Aim of our research line is to resolve the molecular basis of human syndromes with multiple congenital anomalies, which often include mental retardation (MR). We are a young energetic team of multidisciplinary scientists. Our goals are to elucidate novel genes associated with human developmental disorders and to gain insight into normal and disrupted molecular pathways relevant to the disease. Gene identification studies involve state-of-the art genetics and genomics strategies, such as homozygosity mapping and the detection of genomic copy number variations by SNP microarray analysis. The mutated genes are key regulators in development and are found in major developmental signaling pathways. Extensive genotype-phenotype studies have allowed us to dissect some of the distinctive features of the corresponding proteins. In addition, we apply a variety of innovative approaches to further characterize the molecular networks and signaling pathways of the corresponding proteins. Examples include expression profiling in cells and tissues of patients and model organisms, Chromatin Immunoprecipation, lentiviral transductions, shRNA knockdown experiments, and the characterization of Drosophila models (LINK to DROSOPHILA models). Knowledge about these molecular and genetic interactions provides new insights into the large degree of clinical variability that is common to the developmental disorders. Ultimately, these new insights may provide a handle for the development of new strategies for therapeutic interventions.

Selected Publications:

Rinne T, Clements SE, Lamme E, Duijf PH, Bolat E, Meijer R, Scheffer H, Rosser E, Tan TY, McGrath JA, Schalkwijk J, Brunner HG, Zhou H, van Bokhoven H (2008) A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells like syndromes. Hum Mol Genet 17:1968-1977. PubMed

Rinne T, Brunner HG, van Bokhoven H (2007) p63-Associated Disorders. Cell Cycle 6: 262-268. PubMed

van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG (2005) MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet. 37, 465-467. PubMed

van der Zwaag B, Burbach JPH, Scharfe C, Oefner PJ, Brunner HG, Padberg GW, van Bokhoven H. Identifying new candidate genes for hereditary facial paresis on chromosome 3q21-q22 by RNA in situ hybridization in mouse (2005) Genomics 86, 55-67.PubMed

Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B (2006) Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 38, 414-417. PubMed