What causes Fukuyama congenital muscular dystrophy (MDDGA4)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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This is an autosomal recessive disease caused by a mutation in the fukutin gene on 9q that is most common in Japan and is rare elsewhere in the world.

A homozygous ancestral 3-kb retrotransposal insertion into the 3' untranslated region of the gene accounts for 87% of all cases of Fukuyama congenital muscular dystrophy. This results in a relatively mild phenotype.

Patients who are compound heterozygous for the ancestral mutation and another loss-of-function mutation have more severe disease.

Cases of a homozygous null mutation in the fukutin gene resulted in a severe Walker-Warburg syndrome or muscle-eye-brain disease phenotype. There are also cases with a mild limb girdle phenotype now designated as LGMD2M.

Fukutin is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined.

The highest levels of expression are in skeletal muscle, the heart, and the brain. Cellular localization is thought to be within the Golgi apparatus.

Patients with Fukuyama congenital muscular dystrophies have complete loss (or nearly complete loss) of glycosylated α-dystroglycan in the brain and muscle.

α-dystroglycan binding to laminin-α2, neurexin, and agrin is greatly diminished.

Laminin-α2 expression is decreased in muscle.

Electron microscopy reveals a disruption in muscle basal lamina.

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