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.

A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

“…23,24 In addition, DPM3-CDG has been reported in a 27-year-old female with muscle dystrophy and dilated cardiomyopathy, 25 while DOLK-CDG has recently been associated with non-syndromic dilated cardiomyopathy in patients between 5and 18 years of age. 26 Moreover, TUSC3-CDG and MAGT1-CDG are implicated in non-syndromic ID patients, with the age range of 25-62 years. 27 It can be anticipated that other CDG-I subtypes will be associated with mild/moderate phenotypes as well and that mutations in CDG-I genes might be more common than thought until now.…”

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

“…The CTP-dependent dolichol kinase (DK) in yeast is encoded by sec59 (Heller et al, 1992) which, through complementation studies, led to the cloning of human DK (Fernandez et al, 2002;Shridas & Waechter, 2006). Recently, mutations in DK have been associated with autosomal recessive forms of dilated cardiomyopathy in paediatric patients, extending the genes in dolichol biosynthesis associated with CDGs (Denecke & Kranz, 2009;Kapusta et al, 2013;Kranz et al, 2007;Lefeber et al, 2011). (Larkin & Imperiali, 2011).…”

“…S3B) resulted in an astonishing 81 % and 78 % identity, respectively. Although mutations in DK have been associated with autosomal recessive forms of dilated cardiomyopathy (Denecke & Kranz, 2009;Kapusta et al, 2013;Kranz et al, 2007;Lefeber et al, 2011), to date no documented mutations in humans have been found in DOLPP1. Also included on the alignment of DOLPP1 (Fig.…”

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

“…Furthermore, autosomal recessive mutations in genes previously involved in multisystemic congenital (N-) glycosylation disorders (CGDs) have been recently linked to impaired o-mannosylation of dystroglycan, with a cardiomyopathic phenotype, associated to muscular dystrophy (dolichol-phosphatemannose synthase complex, OMIM *605951) 15 or without significant muscular involvement (dolichol kinase, OMIM *610746). 16 Overall, cardiomyopathy is increasingly being described in the clinical spectrum of glycosyltransferase mutations. The present is a report on three unrelated patients affected by cardiomyopathy in association with compound heterozygous POMT1 mutations, with different neuromuscular phenotypes.…”