Inspired by a patient
Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, Pilshofer V, Ceballos-Baumann A, Alhaddad B, Berutti R, Poewe W, Haack TB, Haslinger B, Strom TM, Winkelmann J. Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia. Am J Hum Genet. 2016 Dec 1;99(6):1377-1387.
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.
Despite great advances in dystonia genetics, the underlying genetic causes for most cases of childhood onset dystonia remain unknown. However, a team led by researchers from University College London published a seminal paper describing their discovery of mutations in a gene called KMT2B that cause progressive childhood dystonia. The investigators describe KMT2B dystonia as a dominantly inherited, complex dystonia with onset in infancy or early childhood. Most patients develop dystonia in the limbs as well as pronounced cervical, cranial and laryngeal involvement. Some of the children presented with intellectual disability, psychiatric disorders, specific facial characteristics, and other non-motor symptoms.
The KMT2B protein belongs to a class of proteins that control transcription of other genes and that have been implicated in other neurological conditions. In addition to identifying a novel genetic movement disorder, the team discovered a potentially pivotal mechanism causing dystonia through the so called epigenetic modification. Moreover, it has been observed that although this particular dystonia does not respond well to treatment with oral medications, it can effectively be treated with deep brain stimulation (DBS). The children’s response to DBS was profound, in some cases, restoring the ability to walk.
This work demonstrates yet again that proper diagnosis, including comprehensive genetic testing, is necessary to achieve the most effective therapeutic treatment.