What causes POMGnT1-associated congenital muscular dystrophy (MDDGA3)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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POMGnT1 mutations were first described as the autosomal recessive muscle-eye-brain disease. The gene codes for the glycotransferase O-mannose beta-1,2-N-acetylglucosaminyltransferase that catalyzes the second step of Ser/Thr O-mannosylation (the transfer of N-acetylglucosamine to O-mannose) of α-dystroglycan.

Since the initial description, POMGnT1 mutations have also been described in Walker-Warburg syndrome as well as in a patient presenting with severe autistic features.

One patient with a limb-girdle muscular dystrophy phenotype with no mental retardation was described in an analysis of 92 people with congenital muscular dystrophy. [22] Another patient developed proximal weakness at age 12 years and became wheelchair-bound at age 19 years. She had normal cognitive development and intelligence and has been classified as LGMD 2O. [37]

POMGnT1, like fukutin, is thought to be localized to the Golgi apparatus.

Muscle tissue shows a loss of glycosylated α-dystroglycan; a preserved core α-dystroglycan; and loss of laminin-α2-, agrin-, and neurexin-binding activity.

A genetic model has been generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus, abolishing expression of POMGnT1 mRNA. Glycosylation of α-dystroglycan was reduced, and POMGnT1 -mutant mice had multiple developmental defects in muscle, eyes, and the brain, similar to the phenotypes observed in human muscle-eye-brain disease.

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