RU 2488: Reduced penetrance in hereditary movement disorders: Elucidating mechanisms of endogenous disease protection

An unexpected outcome of recent major sequencing efforts was the finding of a surprisingly large number of carriers of putatively pathogenic mutations who remained free of disease. This phenomenon of reduced penetrance appears to have been substantially underestimated and the concept of protection against disease or delay of its onset age has been largely neglected within the genomic research community. The proposed ProtectMove Research Unit will focus on neurological movement disorders including Parkinson s disease (PD), dystonia, and overlap syndromes. Z1 is the central coordination project, while Z2 builds The ProtectMove Consortium: Longitudinal insights into penetrance of movement disorders and genetic impact at the population level. The INF project addresses common INFormatics requirements. P1: Markers and mechanisms of reduced penetrance in LRRK2 mutation carriers investigates reduced penetrance in the most common form of dominant PD. P2: Reduced penetrance in Parkin and PINK1 deficiency: Prevalence, genetic modifiers, and protective mechanisms aims to identify genetic modifiers influencing the penetrance of heterozygous Parkin and PINK1 mutations in collaboration with P3: Identification and characterization of genes resulting in reduced penetrance in pink1 mutant flies. P4: Identification of genetic modifiers of the penetrance of THAP1 mutations builds on the hypothesis that the penetrance of THAP1 mutations is influenced by the neuronal expression of THAP1 and its target genes. P5 focuses on Genetic modifiers of disease penetrance and expression in X-linked dystonia-parkinsonism. P6: Identification of penetrance- and risk-modifying variants in dystonia using different genome-wide technologies is based on the observation that most of the known mutations in dystonia genes express effects at penetrances of 50% or lower. P7: Identifying determinants of reduced penetrance by analysis of mutation carriers and by age-at-onset analyses in Parkinson s disease aims to identify and further characterize modifiers of penetrance in PD. P8 on Mendelian randomization and path models to infer causality for movement disorders with reduced penetrance addresses an important methodological issue related to the phenomenon of reduced penetrance. Deciphering the mechanisms underlying reduced penetrance of mutations has a high imperative given that reduced penetrance may be viewed as a means of endogenous disease protection. ProtectMove s synergistic effects will arise both from the intensive exchange of ideas, material, and data across projects and from the joint efforts of individually strong research groups, creating a network with powerful international visibility across universities in Northern Germany, Italy, Luxembourg, and Canada. Ten of the 21 principal investigators of the Research Unit are female and six are at the assistant professor or young group leader level ensuring optimal career development of young scientists.