Lefeber, Dirk J. and de Brouwer, Arjan P. M. and Morava, Eva and Riemersma, Moniek and Schuurs-Hoeijmakers, Janneke H. M. and Absmanner, Birgit and Verrijp, Kiek and van den Akker, Willem M. R. and Huijben, Karin and Steenbergen, Gerry and van Reeuwijk, Jeroen and Jozwiak, Adam and Zucker, Nili and Lorber, Avraham and Lammens, Martin and Knopf, Carlos and van Bokhoven, Hans and Gruenewald, Stephanie and Lehle, Ludwig and Kapusta, Livia and Mandel, Hanna and Wevers, Ron A.
Autosomal Recessive Dilated Cardiomyopathy due to DOLK Mutations Results from Abnormal Dystroglycan O-Mannosylation.
PLOS Genetics 7 (12), e1002427.
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.