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Update on KMT2B-Related Dystonia

  • Michael Zech
  • Daniel D. Lam
  • Juliane WinkelmannEmail author
Genetics (V. Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics

Abstract

Purpose of Review

To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome.

Recent Findings

Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2B haploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients.

Summary

DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor.

Keywords

Generalized dystonia Childhood dystonia De novo mutation Haploinsufficiency Lysine-specifc methyltransferase family Deep brain stimulation 

Notes

Acknowledgments

M.Z. was supported by an internal research program at Helmholtz Center Munich, Germany (“Physician Scientists for Groundbreaking Projects”). D.D.L. was supported by DFG grant LA 3830/1-1.

Compliance with Ethical Standards

Conflict of Interest

Michael Zech, Daniel D. Lam, and Juliane Winkelmann each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with animal subjects performed by any of the authors. Signed informed consent for publication of clinical and genetic findings was obtained in accordance with institutional review board regulations and protocols from all the patients (or their legal representatives) who were investigated by the authors and their cooperation partners.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Deciphering Developmental Disorders S. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8.  https://doi.org/10.1038/nature14135.CrossRefGoogle Scholar
  2. 2.
    Epi KC, Epilepsy Phenome/Genome P, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217–21.  https://doi.org/10.1038/nature12439.CrossRefGoogle Scholar
  3. 3.
    Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179–84.  https://doi.org/10.1038/nature12929.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    •• Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99(6):1377–87.  https://doi.org/10.1016/j.ajhg.2016.10.010. In four independent families, this study identifies for the first time protein-truncating variants in the epigenetic regulator gene KMT2B as a cause of childhood-onset generalized dystonia. Based on the observations that (1) KMT2B mRNA levels were significantly decreased in patient-derived cells and (2) literature-reported whole-gene deletions of KMT2B were also associated with dystonia, the authors suggest haploinsufficiency as the most likely molecular mechanism of disease. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    •• Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49(2):223–37.  https://doi.org/10.1038/ng.3740. Published in parallel with the paper by Zech et al., this work decribes a large cohort of dystonia patients harboring protein-truncating, missense, and deletion mutations in KMT2B. The authors provide detailed genotypic and phenotypic data on 28 individuals with DYT-KMT2B, show that KMT2B mutations result in impaired expression of the dystonia-linked genes TOR1A and THAP1, and highlight deep brain stimulation as a promising treatment option for DYT-KMT2B. In addition, they elaborate on the broad spectrum of non-dystonic KMT2B-related symptoms and demonstrate that hypointense basal ganglia lesions can be seen on brain MRI scans of patients with DYT-KMT2B. CrossRefPubMedGoogle Scholar
  6. 6.
    Shen E, Shulha H, Weng Z, Akbarian S. Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652).  https://doi.org/10.1098/rstb.2013.0514.CrossRefGoogle Scholar
  7. 7.
    Ansari KI, Mandal SS. Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 2010;277(8):1790–804.  https://doi.org/10.1111/j.1742-4658.2010.07606.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.  https://doi.org/10.1126/science.1260419.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–76.  https://doi.org/10.1038/nature05453.CrossRefGoogle Scholar
  10. 10.
    Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR, et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development. 2006;133(8):1423–32.  https://doi.org/10.1242/dev.02302.CrossRefPubMedGoogle Scholar
  11. 11.
    Lubitz S, Glaser S, Schaft J, Stewart AF, Anastassiadis K. Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2. Mol Biol Cell. 2007;18(6):2356–66.  https://doi.org/10.1091/mbc.e06-11-1060.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    • Zech M, Jech R, Havrankova P, Fecikova A, Berutti R, Urgosik D, et al. KMT2B rare missense variants in generalized dystonia. Mov Disord. 2017;32(7):1087–91.  https://doi.org/10.1002/mds.27026. This paper highlights the importance of accurate clinical interpretation of KMT2B missense variants, illustrated by clinico-genetic descriptions of three unrelated individuals with novel missense changes in KMT2B. CrossRefPubMedGoogle Scholar
  13. 13.
    Zech M, Jech R, Wagner M, Mantel T, Boesch S, Nocker M, et al. Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing. Neurogenetics. 2017;18(4):195–205.  https://doi.org/10.1007/s10048-017-0521-9.CrossRefPubMedGoogle Scholar
  14. 14.
    • Lange LM, Tunc S, Tennstedt S, Munchau A, Klein C, Assmann B, et al. A novel, in-frame KMT2B deletion in a patient with apparently isolated, generalized dystonia. Mov Disord. 2017;32(10):1495–7.  https://doi.org/10.1002/mds.27137. In this manuscript, the first de novo in-frame deletion variant is reported, and the authors point out that KMT2B mutation should also be considered in the differential diagnosis of seemingly isolated dystonia. CrossRefPubMedGoogle Scholar
  15. 15.
    Dafsari HS, Sprute R, Wunderlich G, Daimaguler HS, Karaca E, Contreras A, et al. Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia. J Hum Genet. 2019;64:803–13.  https://doi.org/10.1038/s10038-019-0625-1.CrossRefPubMedGoogle Scholar
  16. 16.
    • Carecchio M, Invernizzi F, Gonzalez-Latapi P, Panteghini C, Zorzi G, Romito L, et al. Frequency and phenotypic spectrum of KMT2B dystonia in childhood: a single-center cohort study. Mov Disord. 2019.  https://doi.org/10.1002/mds.27771 By identifying 14 novel dystonia patients with. KMT2B variants, this very recent study expands the mutational spectrum of DYT-KMT2B and provides supportive evidence for positive DBS response in DYT-KMT2B. CrossRefGoogle Scholar
  17. 17.
    Bras A, Ribeiro JA, Sobral F, Moreira F, Morgadinho A, Januario C. Early-onset oromandibular-laryngeal dystonia and Charlot gait: new phenotype of DYT-KMT2B. Neurology. 2019;92(19):919.  https://doi.org/10.1212/WNL.0000000000007469.CrossRefPubMedGoogle Scholar
  18. 18.
    Garrido A, Simonet C, Martí MJ, Pérez-Dueñas B, Rumià J, Valldeoriola F. Good response to bilateral GPI-DBS after 2 years in generalized dystonia due to a mutation in the KMT2B gene (DYT28) [abstract]. Mov Disord. 2018;33(suppl 2) https://www.mdsabstracts.org/abstract/good-response-to-bilateral-gpi-dbs-after-2-years-in-generalized-dystonia-due-to-a-mutation-in-the-kmt2b-gene-dyt28/. Accessed 14 June 2019.
  19. 19.
    Hackenberg A, Wagner M, Pahnke J, Zeitler P, Boltshauser E. Low voice, spasmodic dysphonia, and hand dystonia as clinical clues for KMT2B-associated early-onset dystonia. Neuropediatrics. 2018;49(5):356.  https://doi.org/10.1055/s-0038-1661343.CrossRefPubMedGoogle Scholar
  20. 20.
    Baizabal-Carvallo JF, Alonso-Juarez M. Generalized dystonia associated with mutation in the histone methyltransferase gene KMT2B (DYT28) and white matter abnormalities. Parkinsonism Relat Disord. 2018;49:116–7.  https://doi.org/10.1016/j.parkreldis.2018.01.016.CrossRefPubMedGoogle Scholar
  21. 21.
    Klein C, Baumann H, Olschewski L, Hanssen H, Munchau A, Ferbert A, et al. De-novo KMT2B mutation in a consanguineous family: 15-year follow-up of an Afghan dystonia patient. Parkinsonism Relat Disord. 2019;64:337–9.  https://doi.org/10.1016/j.parkreldis.2019.03.018.CrossRefPubMedGoogle Scholar
  22. 22.
    • Dai L, Ding C, Fang F. An inherited KMT2B duplication variant in a Chinese family with dystonia and/or development delay. Parkinsonism Relat Disord. 2018.  https://doi.org/10.1016/j.parkreldis.2018.08.021. This case report shows that KMT2B mutations can cause generalized dystonia and developmental disease without dystonia within the same family. CrossRefGoogle Scholar
  23. 23.
    Zhou XY, Wu JJ, Sun YM. An atypical case of early-onset dystonia with a novel missense variant in KMT2B. Parkinsonism Relat Disord. 2018;63:224–6.  https://doi.org/10.1016/j.parkreldis.2018.09.020.CrossRefPubMedGoogle Scholar
  24. 24.
    Ma J, Wan XH. Novel missense variants in KMT2B in segmental dystonia [abstract]. Mov Disord. 2018;33(suppl 2) https://www.mdsabstracts.org/abstract/novel-missense-variants-in-kmt2b-in-segmental-dystonia/. Accessed 14 June 2019.
  25. 25.
    • Kawarai T, Miyamoto R, Nakagawa E, Koichihara R, Sakamoto T, Mure H, et al. Phenotype variability and allelic heterogeneity in KMT2B-associated disease. Parkinsonism Relat Disord. 2018;52:55–61.  https://doi.org/10.1016/j.parkreldis.2018.03.022. This study confirms high efficacy of DBS treatment in DYT-KMT2B and provides experimental evidence for a role of nonsense-mediated decay in the degregation of truncating variant-bearing KMT2B transcripts. CrossRefPubMedGoogle Scholar
  26. 26.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.  https://doi.org/10.1038/nature19057.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Traynelis J, Silk M, Wang Q, Berkovic SF, Liu L, Ascher DB, et al. Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation. Genome Res. 2017;27(10):1715–29.  https://doi.org/10.1101/gr.226589.117.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, et al. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet. 2012;91(2):358–64.  https://doi.org/10.1016/j.ajhg.2012.06.008.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet. 2012;91(1):73–82.  https://doi.org/10.1016/j.ajhg.2012.05.003.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790–3.  https://doi.org/10.1038/ng.646.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    O'Donnell-Luria AH, Pais LS, Faundes V, Wood JC, Sveden A, Luria V, et al. Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy. Am J Hum Genet. 2019;104(6):1210–22.  https://doi.org/10.1016/j.ajhg.2019.03.021.CrossRefPubMedGoogle Scholar
  32. 32.
    Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J, et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016;19(4):571–7.  https://doi.org/10.1038/nn.4267.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Segel R, Ben-Pazi H, Zeligson S, Fatal-Valevski A, Aran A, Gross-Tsur V, et al. Copy number variations in cryptogenic cerebral palsy. Neurology. 2015;84(16):1660–8.  https://doi.org/10.1212/WNL.0000000000001494.CrossRefPubMedGoogle Scholar
  34. 34.
    Gana S, Veggiotti P, Sciacca G, Fedeli C, Bersano A, Micieli G, et al. 19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias. Eur J Human Gen: EJHG. 2012;20(8):852–6.  https://doi.org/10.1038/ejhg.2012.19.CrossRefGoogle Scholar
  35. 35.
    Melo JB, Estevinho A, Saraiva J, Ramos L, Carreira IM. Cutis Aplasia as a clinical hallmark for the syndrome associated with 19q13.11 deletion: the possible role for UBA2 gene. Mol Cytogenet. 2015;8:21.  https://doi.org/10.1186/s13039-015-0123-x.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhao K, van der Spoel A, Castiglioni C, Gale S, Fujiwara H, Ory DS, et al. 19q13.12 microdeletion syndrome fibroblasts display abnormal storage of cholesterol and sphingolipids in the endo-lysosomal system. Biochim Biophys Acta Mol Basis Dis. 2018;1864(6 Pt A):2108–18.  https://doi.org/10.1016/j.bbadis.2018.03.020.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bragin E, Chatzimichali EA, Wright CF, Hurles ME, Firth HV, Bevan AP, et al. DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation. Nucleic Acids Res. 2014;42(Database issue):D993–D1000.  https://doi.org/10.1093/nar/gkt937.CrossRefPubMedGoogle Scholar
  38. 38.
    Goldsworthy M, Absalom NL, Schroter D, Matthews HC, Bogani D, Moir L, et al. Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice. PLoS One. 2013;8(6):e61870.  https://doi.org/10.1371/journal.pone.0061870.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci. 2013;33(8):3452–64.  https://doi.org/10.1523/JNEUROSCI.3356-12.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    • Barbagiovanni G, Germain PL, Zech M, Atashpaz S, Lo Riso P, D’Antonio-Chronowska A, et al. KMT2B is selectively required for neuronal transdifferentiation, and its loss exposes dystonia candidate genes. Cell Rep. 2018;25(4):988–1001.  https://doi.org/10.1016/j.celrep.2018.09.067. This study elucidates the KMT2B-sensitive transcriptome required for transdifferentiation of murine embryonic fibroblasts into induced neuronal cells and tests the hypothesis that KMT2B target genes could represent novel disease candidates for dystonia. By interrogating 216 targets in whole-exome sequencing data from 225 dystonia patients, the authors prioritize variants in three candidates, namely NOL4, SLC35F1, and SLC40A1. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, et al. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord. 2017;32(4):549–59.  https://doi.org/10.1002/mds.26808.CrossRefPubMedGoogle Scholar
  42. 42.
    Morimoto Y, Ono S, Imamura A, Okazaki Y, Kinoshita A, Mishima H, et al. Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease. Human Genome Variation. 2017;4:17032.  https://doi.org/10.1038/hgv.2017.32.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.  https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Carlston CM, O'Donnell-Luria AH, Underhill HR, Cummings BB, Weisburd B, Minikel EV, et al. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz syndrome. Hum Mutat. 2017;38(5):517–23.  https://doi.org/10.1002/humu.23203.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Faundes V, Newman WG, Bernardini L, Canham N, Clayton-Smith J, Dallapiccola B, et al. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am J Hum Genet. 2018;102(1):175–87.  https://doi.org/10.1016/j.ajhg.2017.11.013.CrossRefPubMedGoogle Scholar
  46. 46.
    Gorman KM, Meyer E, Kurian MA. Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B. Eur J Paediatr Neurol. 2018;22(2):245–56.  https://doi.org/10.1016/j.ejpn.2017.11.009.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Michael Zech
    • 1
    • 2
  • Daniel D. Lam
    • 1
  • Juliane Winkelmann
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Institut für NeurogenomikHelmholtz Zentrum MünchenMunichGermany
  2. 2.Institut für HumangenetikKlinikum rechts der Isar, Technische Universität MünchenMunichGermany
  3. 3.Lehrstuhl für NeurogenetikTechnische Universität MünchenMunichGermany
  4. 4.Munich Cluster for Systems NeurologySyNergyMunichGermany

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