Researchers from the theme Glycosylation Disorders (Dirk Lefeber, Eva Morava and Ron Wevers) worked together with researchers from Israel and the theme Genomic Disorders (Arjan de Brouwer, Hans van Bokhoven) to unravel a novel genetic cause for idiopathic dilated cardiomyopathy. The key to identification of the gene was the finding of abnormal protein N-glycosylation. Extensive biochemical studies in affected heart tissue showed deficient O-mannosylation of alpha-dystroglycan as the underlying pathomechnism of the dilated cardiomyopathy.

Author Summary
Idiopathic dilated cardiomyopathy (DCM) is estimated to be of genetic origin in 20%–48% of the patients. Almost all currently known genetic defects show dominant inheritance, although especially in younger children recessive causes have been proposed to contribute considerably to DCM. Knowledge of the genetic causes and pathophysiological mechanisms is essential for prognosis and treatment. Here, we studied several individual young patients (5–13 years old) with idiopathic and sometimes asymptomatic dilated cardiomyopathy. The key to identification of the gene was the finding of abnormal protein Nglycosylation. Via homozygosity mapping and functional knowledge of the N-glycosylation pathway, the causative gene could be identified as dolichol kinase (DOLK). Since DCM is very rare in N-glycosylation disorders (Congenital Disorders of Glycosylation, CDG) and most patients with CDG present with a multisystem involvement, we studied the underlying pathophysiological cause of this lifethreatening disease. Biochemical experiments in affected heart tissue showed deficient O-mannosylation of alphadystroglycan, which could be correlated with the dilated cardiomyopathy. Our results thus highlight nonsyndromic DCM as a novel presentation of DOLK-CDG, via deficient Omannosylation of alpha-dystroglycan.
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