2.1 DOLK-Congenital Disorder of Glycosylation

At least six mutations in the DOLK gene have been found to cause DOLK-congenital disorder of glycosylation (DOLK-CDG, formerly known as congenital disorder of glycosylation type Im). This condition often causes the heart to be weakened and enlarged (dilated cardiomyopathy), but it can also result in neurological problems as well as other signs and symptoms.

DOLK gene mutations change single protein building blocks (amino acids) in the dolichol kinase enzyme, leading to an enzyme with reduced or absent activity. Without properly functioning dolichol kinase, dolichol phosphate is not produced and glycosylation cannot proceed normally. In particular, a protein known to stabilize heart muscle fibers, called alpha-dystroglycan, has been shown to have reduced glycosylation in people with DOLK-CDG. Impaired glycosylation of alpha-dystroglycan disrupts its normal function, which damages heart muscle fibers as they repeatedly contract and relax. Over time, the fibers weaken and break down, leading to dilated cardiomyopathy. The other signs and symptoms of DOLK-CDG are likely due to the abnormal glycosylation of additional proteins in other organs and tissues.