A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia
2015; Elsevier BV; Volume: 96; Issue: 6 Linguagem: Inglês
10.1016/j.ajhg.2015.04.008
ISSN1537-6605
AutoresNiccolò E. Mencacci, Ignacio Rubio‐Agusti, Anselm A. Zdebik, Friedrich Asmus, Marthe H. R. Ludtmann, Mina Ryten, Vincent Plagnol, Ann‐Kathrin Hauser, Sara Bandrés‐Ciga, Conceição Bettencourt, Paola Forabosco, Deborah Hughes, Marc P. M. Soutar, Kathryn J. Peall, Huw R. Morris, Daniah Trabzuni, Mehmet Tekman, Horia Stanescu, Robert Kleta, Miryam Carecchio, Giovanna Zorzi, Nardo Nardocci, Barbara Garavaglia, Ebba Lohmann, Anne Weißbach, Christine Klein, John Hardy, Alan Pittman, Thomas Foltynie, Andrey Y. Abramov, Thomas Gasser, Kailash P. Bhatia, Nicholas Wood,
Tópico(s)Genetic Neurodegenerative Diseases
ResumoMyoclonus-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. 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. Dystonias are a clinically and genetically heterogeneous group of non-neurodegenerative movement disorders, mainly characterized by involuntary muscle contractions leading to abnormal postures or movements of body segments.1Albanese A. Bhatia K. Bressman S.B. Delong M.R. Fahn S. Fung V.S. Hallett M. Jankovic J. Jinnah H.A. Klein C. et al.Phenomenology and classification of dystonia: a consensus update.Mov. Disord. 2013; 28: 863-873Crossref PubMed Scopus (1374) Google Scholar Mutations in a growing number of genes (recently reviewed by our group)2Charlesworth G. Bhatia K.P. Wood N.W. The genetics of dystonia: new twists in an old tale.Brain. 2013; 136: 2017-2037Crossref PubMed Scopus (86) Google Scholar are responsible for Mendelian forms of dystonia. The identification of these genes allowed the recognition of different cellular pathways involved in the molecular pathogenesis of dystonia, including perturbed synaptic transmission and plasticity, abnormal transcription and cell-cycle regulation, and endoplasmic reticulum (ER) dysfunction.3Ledoux M.S. Dauer W.T. Warner T.T. Emerging common molecular pathways for primary dystonia.Mov. Disord. 2013; 28: 968-981Crossref PubMed Scopus (31) Google Scholar The association with additional movement disorders identifies a sub-group of dystonias, defined as combined dystonias.4Fung V.S. Jinnah H.A. Bhatia K. Vidailhet M. Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes.Mov. Disord. 2013; 28: 889-898Crossref PubMed Scopus (80) Google Scholar Myoclonus-dystonia (M-D [MIM 159900]), one of the combined dystonia syndromes, is a very rare condition with a suggested prevalence of about two per million in Europe.5Asmus F. Gasser T. Inherited myoclonus-dystonia.Adv. Neurol. 2004; 94: 113-119PubMed Google Scholar M-D is clinically characterized by a variable combination of non-epileptic myoclonic jerks, mainly affecting the upper body, and mild to moderate dystonia, usually in the form of cervical dystonia or writer's cramp.6Asmus F. Zimprich A. Tezenas Du Montcel S. Kabus C. Deuschl G. Kupsch A. Ziemann U. Castro M. Kühn A.A. 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Mutat. 2008; 29: 331-332Crossref PubMed Scopus (94) Google Scholar We used a combination of genome-wide linkage analysis and whole-exome sequencing to investigate a previously unpublished dominant British pedigree (shown in Figure 1A) with multiple individuals affected with M-D, in which SCGE mutations (both point mutations and copy number variants) had been excluded. Out of 19 living family members from the index family, 14 were clinically assessed. Assessment included a detailed medical interview and a full-videotaped neurological examination, with focus on movement disorders. All videos were reviewed by two experts in movement disorders, blinded to disease status. The proband (III-2) developed involuntary jerky movements of her arms during childhood. In her late forties she developed constant head jerks and head deviation to the left. In her sixties her speech became involved. On examination at the age of 69 she had spasmodic dysphonia, facial myoclonus, blepharospasm, left torticollis, and frequent irregular dystonic head jerks. There was dystonic hand posturing and low amplitude brief myoclonus. When she walked she presented trunk and bilateral foot dystonia (Movie S1, section 1). Six other family members displayed signs of dystonia and/or myoclonus, and were accordingly categorized as affected (Table 1). Age of onset of movement disorder symptoms ranged from 5 to 20 years. All affected family members initially presented with jerks or a jerky tremor, with mild dystonic features presenting later in life. All cases fulfilled the currently proposed clinical criteria for a definite diagnosis of M-D,15Kinugawa K. Vidailhet M. Clot F. Apartis E. Grabli D. Roze E. Myoclonus-dystonia: an update.Mov. Disord. 2009; 24: 479-489Crossref PubMed Scopus (134) Google Scholar except individual IV-3, who upon examination displayed isolated cervical dystonia, although she reported intermittent jerky arm tremor. Myoclonus involved predominantly the arms (Movie S1, section 2). Dystonia predominantly affected the cranio-cervical region and upper limbs. Older individuals (>60 years; III-2 and III-5) were more severely affected and also showed laryngeal involvement. None of the affected subjects reported improvement of symptoms with alcohol. Subject IV-3 had anxiety and social phobia and subject IV-14 had obsessive traits and suffered from depression. No other individuals presented with psychiatric symptoms.Table 1Clinical Features of Cases Harboring the KCTD17 c.434 G>A p.(Arg145His) MutationSubjectIII-2III-5IV-2IV-3IV-14V-1V-3II.2 (Germany)SexFFMFMFMMAge at last examination (y)7065464435201962Age at onset (y)1061020105510Presenting symptomsJerks; ArmsJerks; ArmsJerks; ArmsJerky tremor; ArmsJerky tremor; ArmsJerks; ArmsJerks; ArmsJerks, ArmsDystonic featuresYesYesYesYesYesYesNoYesInvolved areasCranial, Cervical, Brachial, Truncal, CruralCranial, Cervical, BrachialBrachialCervicalCervical, BrachialBrachialNACranial, Cervical, Brachial, TruncalMyoclonusYesYesYesNoYesYesYesYesInvolved areasCranial, Cervical, BrachialCranial, BrachialBrachialNACranial, BrachialBrachialCervical, BrachialBrachial Open table in a new tab Case IV-12 had strabismus and benign congenital nystagmus, but no signs of M-D. The remaining individuals were asymptomatic and had an entirely normal neurological examination. Samples were collected with the written consent of participants and formal ethical approval by the relevant research ethics committee (UCLH Project ID number 06/N076). DNA of 13 family members and 4 spouses was extracted from blood lymphocytes. A genome-wide linkage analysis was subsequently performed in 7 affected individuals (III-2, III-5, IV-1, IV-3, IV-14, V-1, and V-3), 5 unaffected (III-4, IV-6, IV-8, IV-12, and V-4) and 4 spouses using the HumanCytoSNP-12 DNA Analysis BeadChip Kit (Illumina). The unaffected subject V-2 was not included as she was too young (17 when last examined) to exclude or confirm disease status. Genome-wide multipoint parametric linkage analysis for an autosomal dominant model (estimated allele frequency 0.00001 and 90% penetrance) and haplotype reconstruction were performed with Simwalk2,16Sobel E. Sengul H. Weeks D.E. Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees.Hum. Hered. 2001; 52: 121-131Crossref PubMed Scopus (147) Google Scholar using 24,000 informative single nucleotide polymorphisms (SNPs), equally spaced 0.1cM apart as described before.17Hersheson J. Mencacci N.E. Davis M. MacDonald N. Trabzuni D. Ryten M. Pittman A. Paudel R. Kara E. Fawcett K. et al.Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.Ann. Neurol. 2013; 73: 546-553Crossref PubMed Scopus (127) Google Scholar One single locus with a LOD score > 2 was identified on chromosome 22q13 (LOD score 2.4, the maximal expected value given the pedigree size; see Figure 1C). Fine mapping identified a segregating haplotype delimitated by SNP markers rs926543 and rs3213584 and spanning 6.7 Mb (chr22:36989327–43716324; UCSC hg19 Genome Build), which contained 132 protein-coding genes. In addition, five other regions presented with uninformative multipoint LOD scores, ranging from −0.9 to +0.14, but haplotype analysis excluded segregation of these regions with the disease. We subsequently performed whole-exome sequencing in the two most distantly related affected individuals (V-3 and IV-14). In short, paired-end sequence reads (TruSeq SBS chemistry sequenced on the Illumina HiSeq 2000) were aligned with Novoalign against the reference human genome (UCSC hg19). Duplicate read removal, format conversion, and indexing were performed with Picard. The Genome Analysis Toolkit (GATK) was used to recalibrate base quality scores, perform local realignments around possible indels, and to call and filter the variants. Annotated variant files were generated using ANNOVAR18Wang K. Li M. Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res. 2010; 38: e164Crossref PubMed Scopus (7872) Google Scholar and included a comparison to publicly available databases of sequence variations (dbSNP version 129, 1000 Genomes project, NHLBI Exome Variant Server, and Complete Genomics 69). In silico prediction of pathogenicity was assessed using SIFT,19Kumar P. Henikoff S. Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Nat. Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (5006) Google Scholar PolyPhen2,20Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. Kondrashov A.S. Sunyaev S.R. A method and server for predicting damaging missense mutations.Nat. Methods. 2010; 7: 248-249Crossref PubMed Scopus (9290) Google Scholar MutationTaster,21Schwarz J.M. Cooper D.N. Schuelke M. Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age.Nat. Methods. 2014; 11: 361-362Crossref PubMed Scopus (2421) Google Scholar Provean,22Choi Y. Sims G.E. Murphy S. Miller J.R. Chan A.P. Predicting the functional effect of amino acid substitutions and indels.PLoS ONE. 2012; 7: e46688Crossref PubMed Scopus (1939) Google Scholar and CADD.23Kircher M. Witten D.M. Jain P. O'Roak B.J. Cooper G.M. Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants.Nat. Genet. 2014; 46: 310-315Crossref PubMed Scopus (3676) Google Scholar Conservation of nucleotides involved by variants was scored using Genomic Evolutionary Rate Profiling (GERP).24Davydov E.V. Goode D.L. Sirota M. Cooper G.M. Sidow A. Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++.PLoS Comput. Biol. 2010; 6: e1001025Crossref PubMed Scopus (1008) Google Scholar Interspecies alignment of protein sequences was generated using ClustalW2.25Larkin M.A. Blackshields G. Brown N.P. Chenna R. McGettigan P.A. McWilliam H. Valentin F. Wallace I.M. Wilm A. Lopez R. et al.Clustal W and Clustal X version 2.0.Bioinformatics. 2007; 23: 2947-2948Crossref PubMed Scopus (22516) Google Scholar In total, 83,572,847 (V-3) and 81,527,162 (IV-14) unique reads were generated. According to the Consensus Coding Sequences hg19 definition of the "TruSeq exome," the average read depth of both exomes was >70, >95% of the target bases were covered at a read depth of 2×, and > 90% at a depth of 10×. A total of 22,857 (V-3) and 22,946 (IV-14) exonic/splicing variants were detected. We filtered out all synonymous changes and those not shared by the two affected individuals. Then, under the assumption that the mutation causing this rare autosomal dominant disease is extremely rare and not present in the general population, we also excluded variants that are present in the databases of sequence variations listed above. Furthermore, we excluded variants found in our own in-house exomes (n = 200) from individuals with unrelated diseases. After applying filtering criteria, we were left with only 4 novel missense variants shared by the two affected individuals (see Table S1): c.10976 C>T p.(Ser3659Phe) in FLG (filaggrin; RefSeq NM_002016.1), c.1055 T>G p.(Phe352Cys) in OBSCN (obscurin; RefSeq NM_052843.3), c.1076 A>C p.(Lys359Thr) in LRRC6 (leucine rich repeat containing 6; RefSeq NM_012472.4) and c.434 G>A p.(Arg145His) in KCTD17 (potassium channel tetramerization domain containing 17; RefSeq NM_001282684.1). Of these variants, only the missense change in KCTD17 was located within the linked chromosomal locus on chromosome 22q. We did not detect any shared rare copy-number variants in exome sequencing data using the Exome depth algorithm.26Plagnol V. Curtis J. Epstein M. Mok K.Y. Stebbings E. Grigoriadou S. Wood N.W. Hambleton S. Burns S.O. Thrasher A.J. et al.A robust model for read count data in exome sequencing experiments and implications for copy number variant calling.Bioinformatics. 2012; 28: 2747-2754Crossref PubMed Scopus (385) Google Scholar Sanger sequencing in all available family members confirmed perfect co-segregation of the KCTD17 variant with the disease-phenotype, being the nucleotide change present in all affected individuals and absent in all unaffected (including subject V-2, initially excluded from the linkage analysis). The variant is absent in over 3,700 individuals of European origin without movement disorders, who were exome sequenced by the UCL-exomes consortium, and in a further >61,000 individuals listed in the Exome Aggregation Consortium database (last accessed in March 2015). Although the KCTD17 p.(Arg145His) substitution falls in a functionally uncharacterized portion of the protein, it lies in an extremely conserved amino acid motif, not only completely conserved down to invertebrate species, but also identical in the KCTD17 human paralogs KCTD2 and KCTD5 (Figure 1E). All in silico tools consistently predicted a deleterious effect of the substitution (Table S1). We subsequently sequenced the 9 coding exons of KCTD17 (NM_001282684.1; primers available in Table S2) in a further 87 unrelated probands with familial M-D of British, German, and Italian origin. None of the cases harbored mutations in SGCE. Mutational screening of KCTD17 exon 4 (containing the c.434 G>A mutation) was performed in a further 358 sporadic M-D cases without mutations in SCGE. This analysis revealed the presence of the same KCTD17 mutation, c.434 G>A p.(Arg145His), in the index case of a German family with autosomal dominant M-D (Figure 1B). No further likely pathogenic mutations were identified. The clinical presentation of this case closely resembled that of III-2 and III-5, the older affected subjects from the British family. He reported arm jerks and difficulty writing, starting in childhood. Right torticollis and a jerky head tremor appeared around age 40, becoming progressively debilitating. There was no response to alcohol or psychiatric comorbidities. He underwent surgery for bilateral pallidal deep brain stimulation at age 58, which resulted in marked improvement of cervical dystonia and myoclonus of the upper limbs. Clinical examination at age 62 showed generalized dystonia, with prominent cranio-cervical involvement, and myoclonic jerks involving the upper limbs (Movie S1, section 3). His father was also affected with a movement disorder, presenting with perioral dyskinesia in his forties. The proband's brother had M-D, with similar clinical features, including generalized jerks, cervical dystonia, and dysarthria. Unfortunately, DNA samples of the deceased father and brother were not available for segregation analysis. The 25-year-old proband's only son, who had no signs upon examination, refused genetic testing. Haplotype comparison between the two pedigrees with KCTD17 c.434 G>A p.(Arg145His) was performed with SNP markers located 0.5 Mb up- and downstream of the mutation. This analysis showed that different alleles are located at markers rs5756477 and rs228924, delimitating a small region of ∼100 Kb of a possibly shared haplotype (Table S3). A further analysis with a highly polymorphic microsatellite, located only 1.4 Kb upstream of the 5′ end of KCTD17, revealed that the two pedigrees have different alleles, possibly suggesting the absence of a shared ancestral haplotype and that the variant might have arisen independently in the two pedigrees. Of relevance, the absence of a shared haplotype between the two families would make unlikely that the KCTD17 c.434 G>A p.(Arg145His) mutation is in linkage disequilibrium with the actual causative mutation but not itself pathogenic. We explored the regional distribution of KCTD17 expression in the normal adult human brain. As previously described, we used microarray data (Affymetrix Exon 1.0 ST) from human post-mortem brain tissue collected by the UK Human Brain Expression Consortium (UKBEC).27Trabzuni D. Ryten M. Walker R. Smith C. Imran S. Ramasamy A. Weale M.E. Hardy J. Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies.J. Neurochem. 2011; 119: 275-282Crossref PubMed Scopus (169) Google Scholar KCTD17 mRNA expression throughout the course of human brain development was assessed using the data available in the Human Brain Transcriptome (HBT) database.28Johnson M.B. Kawasawa Y.I. Mason C.E. Krsnik Z. 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Recent work has shown that KCTD17 contributes to the ubiquitin-proteasome machinery, acting as an adaptor for the CUL3-RING E3 ligase and targeting substrates for degradation through polyubiquitinylation.43Kasahara K. Kawakami Y. Kiyono T. Yonemura S. Kawamura Y. Era S. Matsuzaki F. Goshima N. Inagaki M. Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension.Nat. Commun. 2014; 5: 5081Crossref PubMed Scopus (96) Google Scholar Although most of the KCTD17-CUL3 substrates are currently unknown, CUL3 has been implicated in the elaboration of dendrite branching and neurite terminal morphogenesis in Drosophila models.44Zhu S. Perez R. Pan M. Lee T. Requirement of Cul3 for axonal arborization and dendritic elaboration in Drosophila mushroom body neurons.J. Neu
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