Identification of novel dystonia genes in consanguineous families

  • Lohmann, Katja (Principal Investigator (PI))
  • Naz, Sadaf (Associated Staff)

Project: DFG ProjectsDFG Individual Projects

Project Details


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.

Key findings

Das Projekt hatte zum Ziel, neue, rezessive Dystonie-Gene bei 12 konsanguinen Familien mittels Exom-Sequenzierung zu identifizieren. Wir konnten insgesamt 108 DNA-Proben von 15 Familien rekrutieren. Patienten hatten häufig eine komplexe Form der Dystonie, d. h. die Dystonie war durch andere Erkrankungen wie Ataxie, Spasik oder Entwicklungsverzögerung begleitet. Wir konnten die genetische Ursache bei mindestens 9 Familien (60%) aufklären und fanden Mutationen in ATCAY, APTX, CAPN1, ECEL1, GNE, PANK2, PNPLA6, PNPT1 und SACS sowie in MCOLN1 als ein plausibles Kandidaten-Gen. Mutationen in diesen Genen waren bereits bei anderen neurologischen Syndromen gefunden wurden, manche davon auch erst kürzlich wie z.B. CAPN1 oder PNPLA6. ATCAY-Mutationen wiederum waren bisher nur auf einer Insel in der Karibik gefunden wurden, so dass wir hier erstmals zeigen konnten, dass dieses Gen auch bei anderen ethnischen Gruppen relevant ist. Neu ist auch, dass wir für einige der Gene erstmals zeigen konnten, das Mutationen auch zu dystonen Symptomen führen können wie beispielsweise für MCOLN1, PNPLA6, ECEL1 und GNE, d. h. wir konnten hier das phänotypische Spektrum erweitern. Außerdem wurden biallelische Mutationen in COL6A3 während der Projektlaufzeit als eine neue Ursache einer rezessiven Dystonie von einer anderen Arbeitsgruppe publiziert. Wir konnten diesen Befund in unseren eigenen fast 1000 Patienten jedoch nicht bestätigen.

Effective start/end date01.04.1431.03.17

Collaborative partners

  • University of the Punjab Lahore (Associated Staff) (lead)

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Research Area: Medical Genetics

DFG Research Classification Scheme

  • 206-07 Clinical Neurology Neurosurgery and Neuroradiology
  • 206-06 Molecular and Cellular Neurology and Neuropathology


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