Identification of novel dystonia genes in consanguineous families

• Applicant: Professorin Dr. Katja Lohmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256241264

Movement disorders are neurological conditions with involuntary excess or reduction of movement or a combination thereof. Dystonia is a common movement disorder that is characterized by sustained muscle contractions resulting in abnormal postures. Many forms of dystonia that start in childhood have a genetic etiology. However, there is remarkable genetic heterogeneity in dystonia with >35 known genes, mutations in which cause isolated, combined, or complex dystonia syndromes, making molecular diagnosis by conventional genetic methods challenging. Despite the advent of next generation sequencing (NGS) and high heritability of dystonia, the etiology of dystonia currently remains elusive in the majority of patients. Consanguineous families are enriched for patients with recessively inherited conditions and the identification of the underlying genetic cause is facilitated in these families. Notably, there are several examples that disease genes that have been identified using such an approach are also relevant in other populations but are more difficult to detect therein. In collaboration with colleagues from Pakistan and Turkey, we have identified large consanguineous dystonia pedigrees suggesting a homozygous gene defect. Our specific aims for the proposed project are 1) to enroll 12 of these families into the study by performing a standardized neurological examination and obtaining biospecimens; and 2) to use exome sequencing to identify the genetic cause(s). Candidate variants will be validated by segregation analyses using Sanger sequencing and by testing other patients and controls for rare variants within the candidate genes. We expect to a) identify new genes involved in dystonia and b) to broaden the phenotypic spectrum of known genes. These studies may yield better options for diagnosis and treatment and will provide new information on the molecular basis of dystonia.

• DFG Programme: Research Grants
• International Connection: Pakistan
• Participating Person: Professorin Dr. Sadaf Naz