title: Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.
abstract: Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.
authors.affiliation: Department of Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. D.Lefeber@neuro.umcn.nl
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.forename: Birgit
authors.initials: B
authors.lastname: Absmanner
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.forename: Willem M R
authors.initials: WM
authors.lastname: van den Akker
authors.forename: Karin
authors.initials: K
authors.lastname: Huijben
authors.forename: Gerry
authors.initials: G
authors.lastname: Steenbergen
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Adam
authors.initials: A
authors.lastname: Jozwiak
authors.forename: Nili
authors.initials: N
authors.lastname: Zucker
authors.forename: Avraham
authors.initials: A
authors.lastname: Lorber
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: Carlos
authors.initials: C
authors.lastname: Knopf
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grünewald
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lehle
authors.forename: Livia
authors.initials: L
authors.lastname: Kapusta
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D000293:Adolescent; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004288:Dolichol Phosphates / Q000378:metabolism; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D006031:Glycosylation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D012508:Sarcolemma / Q000378:metabolism
chemical_list: D004288:Dolichol Phosphates; D049030:Dystroglycans; D017853:Phosphotransferases (Alcohol Group Acceptor); C020087:dolichol kinase