TY - JOUR
T1 - Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation
AU - Lefeber, Dirk J.
AU - de Brouwer, Arjan P.M.
AU - Morava, Eva
AU - Riemersma, Moniek
AU - Schuurs-Hoeijmakers, Janneke H.M.
AU - Absmanner, Birgit
AU - Verrijp, Kiek
AU - van den Akker, Willem M.R.
AU - Huijben, Karin
AU - Steenbergen, Gerry
AU - van Reeuwijk, Jeroen
AU - Jozwiak, Adam
AU - Zucker, Nili
AU - Lorber, Avraham
AU - Lammens, Martin
AU - Knopf, Carlos
AU - van Bokhoven, Hans
AU - Grünewald, Stephanie
AU - Lehle, Ludwig
AU - Kapusta, Livia
AU - Mandel, Hanna
AU - Wevers, Ron A.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1002427
DO - 10.1371/journal.pgen.1002427
M3 - Article
C2 - 22242004
AN - SCOPUS:84855283452
SN - 1553-7390
VL - 7
JO - PLoS genetics
JF - PLoS genetics
IS - 12
M1 - e1002427
ER -