Project Details
Projekt
Data base, phenotyping and prodromal signs, patient involvement and Ethical, Legal and Social Implications (ELSI) aspects, mutational analysis and induced Pluripotent Stem Cell (iPSC) Core
Applicants
Professorin Dr. Daniela Berg; Professor Dr. Norbert Brüggemann; Professorin Dr. Katja Lohmann; Dr. Philip Seibler
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 287074911
Aside from not manifesting (reduced penetrance), a monogenic disease may show a delayed age at onset or only mild, hardly recognizable signs and symptoms of the disease (variable expressivity). Asymptomatic mutation carriers may display subtle clinical signs that may or may not progress to clinical manifestation. In neurodegenerative movement disorders such as Parkinson’s disease (PD), a prodromal phase typically precedes disease onset. This prodromal phase enables identification of individuals at higher risk to develop PD. Dystonia is usually a non-neurodegenerative disease but also shows reduced penetrance and variable expressivity including only subtle signs in many mutation carriers. A main task of Z2 is the recruitment and detailed clinical characterization of patients, individuals at risk and/or in the prodromal phase, and healthy controls necessary to examine penetrance in its full complexity. We will identify, recruit, and evaluate additional families with monogenic PD and dystonia taking advantage of clinical tools established in the first funding period (Objective 1). We will integrate more information from existing cohorts and add newly recruited cohorts, patients and controls to update and expand the ProtectMove Cohort (Objective 2). The newly developed ProMoveGene database will visualize, summarize, and share genetic and clinical information in a searchable format. It builds on the existing, online MDSGene database which reports genotype-phenotype correlations in published mutation carriers. (Objective 2). To systematically analyze risk and prodromal markers in mutation carriers we will apply the internationally established research criteria for prodromal (idiopathic) PD, which we will adapt to monogenic PD. We will integrate the current knowledge on prodromal PD into our concept of reduced penetrance and expressivity in the ProtectMove PD cohorts (Objective 3). We will use the cohort resources to develop and test ethics protocols for recall by genotype, an important emerging design in cohort studies (Objective 4). Further, we will have two wet-lab cores within Z2. The 'Genetic replication and validation core' will genotype newly identified risk and modifying variants in the new cohorts for replication, validate variants identified by the custom content of the Global Screening Array (GSA), and screen newly collected individuals for disease-relevant mutations to distinguish carriers and non-carriers (Objective 5). Finally, the Induced Pluripotent Stem Cells (iPSC) Core will continue to establish new differentiation protocols, assist in generation of iPSC cells and their differentiation into disease-relevant cell types (Objective 6). The outcomes of these Objectives including the cohort data and biomaterials are relevant to all members of the Research Unit and will contribute to a better understanding of the clinical and molecular spectrum of reduced penetrance and variable expressivity in monogenic PD and dystonia.
DFG Programme
Research Units
