Glycosilation, DOLK-congenital disorder of glycosylation – DOLK gene
DOLK-congenital disorder of glycosylation (DOLK-CDG), also known as congenital disorder of glycosylation type Im or DK1 deficiency, is a hereditary disease that mainly affects the heart, but it can also alter other systems of the organism.
The pattern and severity of the signs and symptoms of this process vary among affected individuals. These signs and symptoms usually manifest in childhood or early childhood, and include dilated cardiomyopathy, recurrent seizures, developmental delay, hypotonia and ichthyosis. Less frequently, affected individuals may have distinctive facial features, kidney disease, hormonal alterations, or eye disorders. Individuals with DOLK-CDG usually don’t survive until adulthood due to complications related to dilated cardiomyopathy, and some don’t survive beyond childhood.
This process is due to mutations in the DOLK (dolichol kinase) gene, located on the long arm of chromosome 9 (9q34.11). This gene encodes the enzyme dolicol kinase, which facilitates the final step of the production of dolicol phosphate, a compound critical for glycosylation. Dolicol kinase is found in the endoplasmic reticulum, involved in the processing and transport of proteins. This enzyme adds a phosphate group to the dolicol compound to produce dolicol phosphate. During glycosylation, sugars are added to dolicol phosphate to constitute the oligosaccharide chain. Once the chain is formed, dolicol phosphate transports the oligosaccharide to the protein that has to be glycosylated and binds to a specific site in the protein. Dolicol phosphate is also needed for the formation of GPI anchors (glycosylphosphatidylinositol).
At least 6 mutations in the DOLK gene have been identified in people with DOLK-CDG. These genetic alterations change amino acids in the dolicol kinase enzyme, which results in an enzyme with reduced or absent activity. As a consequence, dolicol phosphate is not produced and glycosylation cannot be carried out. It has been shown that a protein known to stabilize the heart muscle fibers, called alpha dystroglycan, reduces glycosylation in people with DOLK-CDG. The deterioration of glycosylation of alpha dystroglycan alters its normal function, which damages the muscle fibers of the heart. Over time, the fibers weaken and break, resulting in dilated cardiomyopathy. The other signs and symptoms of DOLK-CDG are probably due to abnormal glycosylation of additional proteins in other organs and tissues.
This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. .
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with DOLK-congenital disorder of glycosylation (DOLK-CDG), by means of the complete PCR amplification of the exons of the DOLK gene, and their subsequent sequencing.
Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).