Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia

Abstract

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.Leu2136Serfs17), 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.Phe2321Serfs93]), 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.

Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study

“…Aside from dystonia, KMT2B variants were frequently associated with additional neurological features, such as mild intellectual disability, short stature, brisk reflexes in the lower limbs, and minor facial dysmorphic features. Consistently, among 6 mutation carriers reported on by Zech and colleagues, short stature was observed in 3, and intellectual disability in 4, whereas Meyer and colleagues reported these features in 55% and 11% of cases, respectively …”

“…). Four asymptomatic carriers have been previously reported, suggesting incomplete disease penetrance of some KMT2B mutations, a well‐known mechanism described for other dystonia‐related genes, such as DYT1 and THAP1 . Somatic mosaicism may explain incomplete disease penetrance in asymptomatic carriers; however, no cases of KMT2B somatic mosaicism have been reported so far.…”

KMT2B: A new twist in dystonia genetics

“…Recently, 2 groups reported autosomal‐dominant mutations, mostly de novo , in the lysine methyltransferase 2B ( KM2TB ) gene in a total of 33 patients with early‐onset (1‐11 years), combined dystonia …”

“…Some patients had dystonic tremor and jerks, clinically appearing as myoclonus. Intercurrent illness or physical stressors like surgery exacerbated dystonia symptoms …”

Measuring “Intolerance to Mutation” in Human Genetics

“…pLI is also increasingly used in clinical annotation and in databases of mouse models as indicative of haploinsufficiency and dosage sensitivity [46][47][48][49][50] . In fact, however, pLI and related measures are not directly informative about dominance effects on fitness, let alone about the degree of haploinsufficiency with respect to a phenotype, and instead reflect only the strength of selection acting in heterozygotes.…”