https://hdl.handle.net/10481/23916 2026-04-06T14:37:45Z 2026-04-06T14:37:45Z Mencacci, Niccolo E. Bandrés Ciga, Sara https://hdl.handle.net/10481/63188 2021-06-15T13:14:56Z

A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia Mencacci, Niccolo E.; Bandrés Ciga, Sara Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. We would like to extend our thanks to the individuals whose participation made this research possible. This work was supported financially by a Medical Research Council/Wellcome Trust Strategic Award (WT089698/Z/09/Z) and a grant from the Bachman-Strauss Dystonia Parkinsonism Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The work was undertaken at University College London Hospitals (UCLH) and University College London (UCL), who receive support from the Department of Health's NIHR Biomedical Research Center's funding streams. E.L. and T.G. are supported by a grant from the Dystonia Medical Research Foundation (DMRF). C.K. is the recipient of a career development award from the Herman and Lilly Schilling Foundation. A.M.P. is funded by the Reta Lila Weston Trust. S.B.C. held a FPU fellowship from the Spanish Ministry of Education and Science jointly with a short-term stay grant by Cei-BioTic and University of Granada. Next Generation Sequencing was performed at the UCL Institute of Neurology Sequencing Facility. We thank the UCL-Exomes Consortium for providing the exome sequencing data of UK population controls. Expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises J.H., M.R., Michael Weale, D.T., Adaikalavan Ramasamy, Colin Smith, and Robert Walker. UKBEC members are affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King's College London (M.R., Adaikalavan Ramasamy, and Michael Weale), and the University of Edinburgh (Colin Smith and Robert Walker). We thank Miss Elisavet Preza for providing help with the skin biopsy preparation.

Luna-Sánchez, Marta Hidalgo Gutiérrez, Agustín Chaves Serrano, Julio Barriocanal Casado, Eliana Santos Fandila, Ángela Romero Pérez, Miguel Sayed, Ramy K. A. Duarte, Juan Escames Rosa, Germaine Acuña Castroviejo, Darío Cuadros López, José Luis https://hdl.handle.net/10481/58176 2021-06-16T09:23:39Z

CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome Luna-Sánchez, Marta; Hidalgo Gutiérrez, Agustín; Chaves Serrano, Julio; Barriocanal Casado, Eliana; Santos Fandila, Ángela; Romero Pérez, Miguel; Sayed, Ramy K. A.; Duarte, Juan; Escames Rosa, Germaine; Acuña Castroviejo, Darío; Cuadros López, José Luis Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome.