UCL Queen Square Institute of Neurology


Mutations in two novel genes cause primary dystonia

15 May 2015

Researchers at the UCL Institute of Neurology have identified mutations in hippocalcin (HPCA) and potassium channel tetramerization domain containing 17 (KCTD17) as novel causes of primary dystonia, a disorder which afflicts over 70,000 people in the UK alone.

The studies, done by Dr Gavin Charlesworth and Dr Niccolo E. Mencacci under the supervision of Professor Nick Wood and Professor Kailash Bhatia, were both published as separate papers in the American Journal of Human Genetics.

In the first study, recessive mutations in the gene HPCA were identified as the cause of childhood onset isolated dystonia in three siblings from a consanguineous family of Middle Eastern origin. Subsequently, mutations in the same gene were also detected in a second family exhibiting young-onset dystonia, confirming HPCA as the responsible gene.

In the second study, a missense mutation in KCTD17 was identified as the cause in a very large British family with dominantly inherited myoclonus-dystonia – a condition in which dystonia is present together with non-epileptic myoclonic jerks. This same mutation was then detected in a separate, unrelated family originating from Germany who exhibited the same condition.

Both studies used the next-generation exome sequencing platform at Institute of Neurology in combination with more traditional genetic linkage studies.

Dystonia is the 3rd most common movement disorder (after Parkinson’s disease and tremor) and clinically results in sustained or intermittent muscle contractions, which cause abnormal movements and postures. Given the absence of neurodegeneration, dystonia is believed to be a neuronal network disorder of the basal ganglia connections, but the exact cellular mechanisms underlying the condition remain unclear. As has been the case with other conditions, the identification of novel disease-causing genes associated with dystonia offers new insights into the cellular pathways critical to development of the disease.

At present, little is known about the cellular functions of HPCA and KCTD17 and their mutation leads to the development of dystonia. Nonetheless, both genes were shown to be highly expressed in the brain, and, in particular, the basal ganglia (an area intimately connected with movement disorders). In the case of both genes, experiments in cell models demonstrated significant abnormalities in intra-cellular calcium signaling, adding weight to previous data suggesting that perturbed calcium homeostasis may play a central role in the pathogenesis of this condition.

To gain further preliminary insight into the biology of KCTD17 and HPCA, weighted gene co-expression network analysis (WGCNA) was used. WGCNA uses brain regional mRNA expression data to generate modules of genes that are highly co-expressed and co-regulated and therefore likely to be functionally related. The analysis was performed based on the dataset generated by the UK Brain Expression Consortium (UKBEC) using samples from more than a hundred neuropathologically normal brains. This analysis showed that, in the basal ganglia KCTD17 and HPCA form part of the same gene network and that this network is significantly enriched for genes involved in postsynaptic regulation of dopaminergic transmission.

Further information:

Image: Network Representation of the Putamen KCTD17-Containing Gene