A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia PMID: 25983243

Target-related Cytokines

2026-09-23

A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia

Am J Hum Genet. 2015 Jun 4;96(6):938-47. doi: 10.1016/j.ajhg.2015.04.008.

Niccolo E Mencacci ¹ , Ignacio Rubio-Agusti ² , Anselm Zdebik ³ , Friedrich Asmus ⁴ , Marthe H R Ludtmann ⁵ , Mina Ryten ⁶ , Vincent Plagnol ⁷ , Ann-Kathrin Hauser ⁴ , Sara Bandres-Ciga ⁸ , Conceição Bettencourt ⁵ , Paola Forabosco ⁹ , Deborah Hughes ⁵ , Marc M P Soutar ⁵ , Kathryn Peall ¹⁰ , Huw R Morris ¹¹ , Daniah Trabzuni ¹² , Mehmet Tekman ¹³ , Horia C Stanescu ¹³ , Robert Kleta ¹³ , Miryam Carecchio ¹⁴ , Giovanna Zorzi ¹⁵ , Nardo Nardocci ¹⁵ , Barbara Garavaglia ¹⁶ , Ebba Lohmann ⁴ , Anne Weissbach ¹⁷ , Christine Klein ¹⁷ , John Hardy ¹⁸ , Alan M Pittman ¹⁸ , Thomas Foltynie ¹⁹ , Andrey Y Abramov ⁵ , Thomas Gasser ⁴ , Kailash P Bhatia ²⁰ , Nicholas W Wood ²¹

Affiliations

1. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Universita degli Studi di Milano, 20149 Milan, Italy.
2. Unidad de Trastornos del Movimiento, Hospital Universitario La Fe, 46026 Valencia, Spain; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
3. Department of Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK; Centre for Nephrology, University College London, NW3 2PF London, UK.
4. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
5. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
6. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, SE1 7EH London, UK.
7. UCL Genetics Institute, WC1E 6BT London, UK.
8. Department of Physiology and Institute of Neurosciences Federico-Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, 18071 Granada, Spain.
9. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Cagliari, Italy.
10. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CF24 4HQ Cardiff, UK.
11. Department of Clinical Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
12. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
13. Centre for Nephrology, University College London, NW3 2PF London, UK.
14. Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
15. Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
16. Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
17. Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
18. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, WC1N 3BG London, UK.
19. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
20. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK. Electronic address: [email protected].
21. Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK. Electronic address: [email protected].

Abstract

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.