Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia.
Age of Onset
Alleles
Child
Child, Preschool
Disease Progression
Dystonia
/ diagnosis
Female
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genomics
/ methods
Genotype
Histone-Lysine N-Methyltransferase
/ chemistry
Humans
Male
Models, Molecular
Mutation
Neuroimaging
/ methods
Pedigree
Phenotype
Protein Conformation
Structure-Activity Relationship
Symptom Assessment
Whole Genome Sequencing
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
06
03
2019
accepted:
21
05
2019
revised:
09
05
2019
pubmed:
6
6
2019
medline:
18
12
2019
entrez:
6
6
2019
Statut:
ppublish
Résumé
Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.
Identifiants
pubmed: 31165786
doi: 10.1038/s10038-019-0625-1
pii: 10.1038/s10038-019-0625-1
doi:
Substances chimiques
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
KMT2B protein, human
EC 2.1.1.43
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
803-813Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CI 218/1-1
Commentaires et corrections
Type : ErratumIn
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