Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation

Area of Science:

• Genetics
• Molecular Biology
• Cardiology

Background:

• Autosomal recessive dilated cardiomyopathy (DCM) is a rare but significant cause of heart failure in children.
• Genetic underpinnings for DCM are often elusive, hindering diagnosis and treatment.
• Congenital Disorders of Glycosylation (CDG) are a group of rare inherited metabolic diseases affecting protein and lipid glycosylation.

Purpose of the Study:

• To identify the genetic cause of nonsyndromic DCM in young patients.
• To investigate the molecular mechanisms underlying DCM in affected individuals.
• To explore the link between glycosylation defects and cardiac dysfunction.

Main Methods:

• Genetic analysis including homozygosity mapping and mutation identification in consanguineous families.
• Metabolic investigations to assess protein N-glycosylation.
• Enzyme activity assays using patient-derived fibroblasts.
• Analysis of glycosylation pathways in biopsied heart tissue.

Main Results:

• Identified pathogenic mutations in the DOLK gene in 11 young patients with DCM.
• Confirmed dolichol kinase deficiency in all affected individuals.
• Demonstrated reduced O-mannosylation of alpha-dystroglycan and impaired laminin-binding capacity in heart tissue.
• Observed a distinct presentation of nonsyndromic DCM, differing from typical multisystem CDG.

Conclusions:

• Autosomal recessive mutations in DOLK are a novel genetic cause of nonsyndromic dilated cardiomyopathy in children.
• Combined deficiencies in protein N-glycosylation and alpha-dystroglycan O-mannosylation contribute to DCM pathogenesis.
• This finding expands the understanding of CDG and its cardiac manifestations.