DOLK – DK1-congenital Disorder of Glycosylation

DOLK encodes dolichol kinase, essential for dolichyl phosphate synthesis in the N-glycosylation pathway. Biallelic pathogenic variants result in DK1-congenital disorder of glycosylation, a subtype characterised by predominant cardiac involvement.

Cardiac manifestations were reported in nine patients from three unrelated Israeli families, all with novel homozygous DOLK mutations ([PMID:22327749]). The spectrum ranged from mild discrete dilated cardiomyopathy to acute decompensation with heart failure, including successful transplantation in several cases and unexpected deaths soon after presentation ([PMID:22327749]).

Inheritance is autosomal recessive with homozygous loss-of-function variants; segregation data are limited to affected siblings in the three families and warrant further study.

Specific variant sequences were not detailed in the abstract, though all alleles were described as novel and homozygous, indicating a need for comprehensive variant cataloguing in future cohorts.

Functional studies in Saccharomyces cerevisiae demonstrate that sec59 mutants (the DOLK homolog) exhibit temperature-sensitive defects in oligosaccharide assembly and impaired N-glycosylation, with restoration of function upon expression of wild-type kinase confirming a loss-of-function mechanism ([PMID:8108435]).

Integration of genetic case series and yeast functional data supports a moderate clinical validity for DOLK in DK1-CDG. Testing for DOLK variants is recommended in unexplained dilated cardiomyopathy cases. Key take-home: Biallelic DOLK mutations cause an autosomal recessive CDG with predominant cardiac phenotype, guiding targeted genetic diagnosis and management.

References

• Heart failure reviews • 2013 • From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG). PMID:22327749
• Proceedings of the National Academy of Sciences of the United States of America • 1994 • A screen for yeast mutants with defects in the dolichol-mediated pathway for N-glycosylation. PMID:8108435

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