A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia

Niccolo E. Mencacci, Ignacio Rubio-Agusti, Anselm Zdebik, Friedrich Asmus, Marthe H R Ludtmann, Mina Ryten, Vincent Plagnol, Ann Kathrin Hauser, Sara Bandres-Ciga, Conceição Bettencourt, Paola Forabosco, Deborah Hughes, Marc M P Soutar, Kathryn Peall, Huw R. Morris, Daniah Trabzuni, Mehmet Tekman, Horia C. Stanescu, Robert Kleta, Miryam CarecchioGiovanna Zorzi, Nardo Nardocci, Barbara Garavaglia, Ebba Lohmann, Anne Weissbach, Christine Klein, John Hardy, Alan M. Pittman, Thomas Foltynie, Andrey Y. Abramov, Thomas Gasser, Kailash P. Bhatia, Nicholas W. Wood

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)938-947
Number of pages10
JournalAmerican Journal of Human Genetics
Volume96
Issue number6
DOIs
Publication statusPublished - Jun 4 2015

Fingerprint

Missense Mutation
Mutation
Myoclonus
Dystonia
Putamen
Exome
Dystonic Disorders
Calcium Signaling
Gene Regulatory Networks
Movement Disorders
Brain
Pedigree
Upper Extremity
Synaptic Transmission
Endoplasmic Reticulum
Genes
Myoclonic dystonia
Fibroblasts
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mencacci, N. E., Rubio-Agusti, I., Zdebik, A., Asmus, F., Ludtmann, M. H. R., Ryten, M., ... Wood, N. W. (2015). A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. American Journal of Human Genetics, 96(6), 938-947. https://doi.org/10.1016/j.ajhg.2015.04.008

A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. / Mencacci, Niccolo E.; Rubio-Agusti, Ignacio; Zdebik, Anselm; Asmus, Friedrich; Ludtmann, Marthe H R; Ryten, Mina; Plagnol, Vincent; Hauser, Ann Kathrin; Bandres-Ciga, Sara; Bettencourt, Conceição; Forabosco, Paola; Hughes, Deborah; Soutar, Marc M P; Peall, Kathryn; Morris, Huw R.; Trabzuni, Daniah; Tekman, Mehmet; Stanescu, Horia C.; Kleta, Robert; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Garavaglia, Barbara; Lohmann, Ebba; Weissbach, Anne; Klein, Christine; Hardy, John; Pittman, Alan M.; Foltynie, Thomas; Abramov, Andrey Y.; Gasser, Thomas; Bhatia, Kailash P.; Wood, Nicholas W.

In: American Journal of Human Genetics, Vol. 96, No. 6, 04.06.2015, p. 938-947.

Research output: Contribution to journalArticle

Mencacci, NE, Rubio-Agusti, I, Zdebik, A, Asmus, F, Ludtmann, MHR, Ryten, M, Plagnol, V, Hauser, AK, Bandres-Ciga, S, Bettencourt, C, Forabosco, P, Hughes, D, Soutar, MMP, Peall, K, Morris, HR, Trabzuni, D, Tekman, M, Stanescu, HC, Kleta, R, Carecchio, M, Zorzi, G, Nardocci, N, Garavaglia, B, Lohmann, E, Weissbach, A, Klein, C, Hardy, J, Pittman, AM, Foltynie, T, Abramov, AY, Gasser, T, Bhatia, KP & Wood, NW 2015, 'A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia', American Journal of Human Genetics, vol. 96, no. 6, pp. 938-947. https://doi.org/10.1016/j.ajhg.2015.04.008
Mencacci NE, Rubio-Agusti I, Zdebik A, Asmus F, Ludtmann MHR, Ryten M et al. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. American Journal of Human Genetics. 2015 Jun 4;96(6):938-947. https://doi.org/10.1016/j.ajhg.2015.04.008
Mencacci, Niccolo E. ; Rubio-Agusti, Ignacio ; Zdebik, Anselm ; Asmus, Friedrich ; Ludtmann, Marthe H R ; Ryten, Mina ; Plagnol, Vincent ; Hauser, Ann Kathrin ; Bandres-Ciga, Sara ; Bettencourt, Conceição ; Forabosco, Paola ; Hughes, Deborah ; Soutar, Marc M P ; Peall, Kathryn ; Morris, Huw R. ; Trabzuni, Daniah ; Tekman, Mehmet ; Stanescu, Horia C. ; Kleta, Robert ; Carecchio, Miryam ; Zorzi, Giovanna ; Nardocci, Nardo ; Garavaglia, Barbara ; Lohmann, Ebba ; Weissbach, Anne ; Klein, Christine ; Hardy, John ; Pittman, Alan M. ; Foltynie, Thomas ; Abramov, Andrey Y. ; Gasser, Thomas ; Bhatia, Kailash P. ; Wood, Nicholas W. / A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 6. pp. 938-947.
@article{f81ab8e146dd47cf8511770044309050,
title = "A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia",
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.",
author = "Mencacci, {Niccolo E.} and Ignacio Rubio-Agusti and Anselm Zdebik and Friedrich Asmus and Ludtmann, {Marthe H R} and Mina Ryten and Vincent Plagnol and Hauser, {Ann Kathrin} and Sara Bandres-Ciga and Concei{\cc}{\~a}o Bettencourt and Paola Forabosco and Deborah Hughes and Soutar, {Marc M P} and Kathryn Peall and Morris, {Huw R.} and Daniah Trabzuni and Mehmet Tekman and Stanescu, {Horia C.} and Robert Kleta and Miryam Carecchio and Giovanna Zorzi and Nardo Nardocci and Barbara Garavaglia and Ebba Lohmann and Anne Weissbach and Christine Klein and John Hardy and Pittman, {Alan M.} and Thomas Foltynie and Abramov, {Andrey Y.} and Thomas Gasser and Bhatia, {Kailash P.} and Wood, {Nicholas W.}",
year = "2015",
month = "6",
day = "4",
doi = "10.1016/j.ajhg.2015.04.008",
language = "English",
volume = "96",
pages = "938--947",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia

AU - Mencacci, Niccolo E.

AU - Rubio-Agusti, Ignacio

AU - Zdebik, Anselm

AU - Asmus, Friedrich

AU - Ludtmann, Marthe H R

AU - Ryten, Mina

AU - Plagnol, Vincent

AU - Hauser, Ann Kathrin

AU - Bandres-Ciga, Sara

AU - Bettencourt, Conceição

AU - Forabosco, Paola

AU - Hughes, Deborah

AU - Soutar, Marc M P

AU - Peall, Kathryn

AU - Morris, Huw R.

AU - Trabzuni, Daniah

AU - Tekman, Mehmet

AU - Stanescu, Horia C.

AU - Kleta, Robert

AU - Carecchio, Miryam

AU - Zorzi, Giovanna

AU - Nardocci, Nardo

AU - Garavaglia, Barbara

AU - Lohmann, Ebba

AU - Weissbach, Anne

AU - Klein, Christine

AU - Hardy, John

AU - Pittman, Alan M.

AU - Foltynie, Thomas

AU - Abramov, Andrey Y.

AU - Gasser, Thomas

AU - Bhatia, Kailash P.

AU - Wood, Nicholas W.

PY - 2015/6/4

Y1 - 2015/6/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84964696942&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964696942&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.04.008

DO - 10.1016/j.ajhg.2015.04.008

M3 - Article

C2 - 25983243

AN - SCOPUS:84964696942

VL - 96

SP - 938

EP - 947

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -