Universität zu Köln

Dafsari, Hormos Salimi, Sprute, Rosanne ORCID: 0000-0003-2457-6437, Wunderlich, Gilbert, Daimagueler, Huelya-Sevcan, Karaca, Ezgi ORCID: 0000-0002-4926-7991, Contreras, Adriana, Becker, Kerstin, Schulze-Rhonhof, Mira, Kiening, Karl, Karakulak, Tulay ORCID: 0000-0002-4644-2774, Kloss, Manja, Horn, Annette, Pauls, Amande, Nuernberg, Peter, Altmueller, Janine, Thiele, Holger, Assmann, Birgit, Koy, Anne and Cirak, Sebahattin (2019). Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia. J. Hum. Genet., 64 (8). S. 803 - 814. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1435-232X

Full text not available from this repository.

Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dafsari, Hormos Salimi UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprute, Rosanne UNSPECIFIED orcid.org/0000-0003-2457-6437 UNSPECIFIED Wunderlich, Gilbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Daimagueler, Huelya-Sevcan UNSPECIFIED UNSPECIFIED UNSPECIFIED Karaca, Ezgi UNSPECIFIED orcid.org/0000-0002-4926-7991 UNSPECIFIED Contreras, Adriana UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulze-Rhonhof, Mira UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiening, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Karakulak, Tulay UNSPECIFIED orcid.org/0000-0002-4644-2774 UNSPECIFIED Kloss, Manja UNSPECIFIED UNSPECIFIED UNSPECIFIED Horn, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauls, Amande UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Assmann, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Koy, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-133857
DOI:	10.1038/s10038-019-0625-1
Journal or Publication Title:	J. Hum. Genet.
Volume:	64
Number:	8
Page Range:	S. 803 - 814
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	NEW YORK
ISSN:	1435-232X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEEP-BRAIN-STIMULATION; PROTEIN; MINERALIZATION; ASSOCIATION; VARIANTS; SEQUENCE; COMPLEX; SERVER; GENE Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13385