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Zech, M. ; Boesch, S.* ; Maier, E.M.* ; Borggraefe, I.* ; Vill, K.* ; Laccone, F.* ; Pilshofer, V.* ; Ceballos-Baumann, A.* ; Alhaddad, B.* ; Berutti, R. ; Poewe, W.* ; Haack, T.B. ; Haslinger, B.* ; Strom, T.M. ; Winkelmann, J.


Am. J. Hum. Genet. 99, 1377-1387 (2016)
Verlagsversion Forschungsdaten DOI
Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs∗17), in KMT2B, encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B—one de novo nonsense mutation (c.1633C>T [p.Arg545∗]), one de novo essential splice-site mutation (c.7050−2A>G [p.Phe2321Serfs∗93]), and one inherited nonsense mutation (c.2428C>T [p.Gln810∗]) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C>T (p.Gln810∗) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B. Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter De-novo Mutations; Intellectual Disability; Microdeletion Syndrome; Memory Formation; Critical Region; Stem-cells; Schizophrenia; Disease; Gene; Mll2
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 99, Heft: 6, Seiten: 1377-1387 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY