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.
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.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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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.
https://www.dystonia-foundation.org/site/news/30096
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