Glycogen storage disorders are inborn errors of metabolism that typically affect the cellular architecture and function of the liver or kidney. However, some of these diseases manifest in skeletal or cardiac myocytes, where they lead to altered electrophysiological responses, muscle weakness, and hypertrophy. Arad et al. show here that a cardiac-specific glycogen storage disease occurs in individuals with any of 3 dominantly acting missense mutations affecting conserved residues in PRKAG2. This gene encodes a regulatory subunit of AMPK, the AMP-activated protein kinase. Like its yeast homolog, Snf4, PRKAG2 apparently regulates glucose metabolism by associating with AMPK's catalytic subunits. By introducing the human disease mutations into Snf4, the authors show here that the changes render the regulatory subunit constitutively active, causing it to bind to a catalytic subunit even in cells that are supplied abundant glucose. Interestingly, one of the PRKAG2 mutations has been found previously in the related gene PRKAG3, where it causes a skeletal muscle-specific defect of domesticated pigs. Despite some similarities with diseases linked to sarcomere protein genes, which also present with cardiac hypertrophy, Arad et al. note that this glycogen storage disease has a different etiology and does not disrupt the structure of cardiac sarcomeres.

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Contact: John Ashkenas
scied@the-jci.org
416-946-7593
Journal of Clinical Investigation
30-Jan-2002

Page: 1
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