What causes glycosyltransferase deficiency congenital muscular dystrophy (CMD)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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Answer

All of these congenital muscular dystrophies are thought to be due to mutations in glycotransferase genes or accessory proteins of glycotransferases, which result in abnormal glycosylation and therefore abnormal function of α-dystroglycan. Immunolabeling of α-dystroglycan correlates with clinical severity (cases with absent labeling had the most severe phenotype) in patients with mutations of POMT1, POMT2, and POMGnT1, but not in patients with mutations in fukutin, FKRP, or LARGE. [36]

More severe phenotypes appear to be associated with mutations predicted to result in a severe disruption of the respective genes. [24]

α-dystroglycan is thought to act as a link between the basal lamina and the cytoskeleton. It is present in muscle, nerve, and brain. In these congenital muscular dystrophies, α-dystroglycan is often correctly localized to the muscle cell membrane, but its function is impaired.

α-dystroglycan (and β-dystroglycan) are transcribed from the gene DAG1 and cleaved into 2 components.

The C-terminal region of α-dystroglycan binds β-dystroglycan independent of glycosylation.

Binding of α-dystroglycan to extracellular matrix proteins laminin, neurexin, agrin, and perlecan is glycosylation dependent.

α-dystroglycan is heavily glycosylated.

  • The predicted molecular weight of α-dystroglycan is 75 kd, but its molecular weight on Western blot testing is 120-156 kd, suggesting it is heavily glycosylated.

  • α-dystroglycan has a mucinlike domain with several serine or threonine residues as potential O-glycosylation sites.

  • A unique carbohydrate structure containing O-linked mannose has only been found on α-dystroglycan in mammals. This linkage is likely disrupted in the congenital muscular dystrophies caused by defects in O-glycosylation.

α-dystroglycan is crucial in the formation and maintenance of the basement membrane. Complete disruption of α-dystroglycan in mice is embryonically lethal because of improper formation of the Reichert membrane, which is the basement membrane that separates the embryo from the maternal circulation. Similarly, disruption of the POMT1 gene (see below) in a mouse model also results in embryonic lethality due to inability to form the Reichert membrane.


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