Mutations in the δ-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2)

Abstract

The dystrophin-based membrane cytoskeleton of muscle fibers has emerged as a critical multi-protein complex which seems to impart structural integrity on the muscle fiber plasma membrane. Deficiency of dystrophin causes the most common types of muscular dystrophy, Duchenne and Becker muscular dystrophies. Muscular dystrophy patients showing normal dystrophin protein and gene analysis are generally isolated cases with a presumed autosomal recessive inheritance pattern (limb-girdle muscular dystrophy). Recently, linkage and candidate gene analyses have shown that some cases of limb-girdle muscular dystrophy can be caused by deficiency of other components of the dystrophin membrane cytoskeleton. The most recently identified component, delta-sarcoglycan, has been found to show mutations in a series of Brazilian muscular dystrophy patients. All patients were homozygous for a protein-truncating carboxy-terminal mutation, and showed a deficiency of the four sarcoglycan proteins. To determine if delta-sarcoglycan deficiency occurred in other world populations, to identify the range of mutations and clinical phenotypes, and to test for the biochemical consequences of delta-sarcoglycan gene mutations, we studied Duchenne-like and limb-girdle muscular dystrophy patients who we had previously shown not to exhibit gene mutations of dystrophin, alpha-, beta-, or gamma-sarcoglycan for delta-sarcoglycan mutations (n = 54). We identified two American patients with novel nonsense mutations of delta-sarcoglycan (W30X, R165X). One was apparently homozygous, and we show likely consanguinity through homozygosity for 13 microsatellite loci covering a 38 cM region of chromosome 5. The second was heterozygous. Both were girls who showed clinical symptoms consistent with Duchenne muscular dystrophy in males. Our data shows that delta-sarcoglycan deficiency occurs in other world populations, and that most or all patients show a deficiency of the entire sarcoglycan complex, adding support to the hypothesis that these proteins function as a tetrameric unit.

SERCA2a Gene Therapy Can Improve Symptomatic Heart Failure in δ-Sarcoglycan-Deficient Animals

“…The sarcoglycan complex constitutes a transmembrane component of the dystrophin-glycoprotein complex (DGC), which links the cytoskeleton to the extracellular matrix (Wheeler and McNally, 2003). d-Sarcoglycan (d-SG) mutations may lead most frequently to a complete loss or a strong reduction of the whole SG complex (Duggan et al, 1997) and are associated with a form of autosomal recessive limb-girdle muscular dystrophy 2F (LGMD2F). Patients with LGMD2F present progressive weakness, with respiratory failure and dilated cardiomyopathy (Nigro et al, 1996).…”

rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy

“…The disease is caused by mutations in a number of responsible genes, [13][14][15][16][17] including sarcoglycan genes ␣ (LGMD 2D), ␤ (LGMD 2E), ␥ (LGMD 2C) and ␦ (LGMD 2F), respectively. 14,[18][19][20][21][22][23][24] While the phenotype of the sarcoglycanopathies is variable, patients often show a severe progression, with fatality in the second or third decade.…”

Confocal analysis of the dystrophin protein complex in muscular dystrophy

“…16,34,35,37,40,42 Loss of any single component of the sarcoglycan complex results in a decrease of the expression of other components, 5,28,30,31 and mutations within this complex are now recognized as a primary cause of four autosomal recessive forms of dystrophy resembling Duchenne and Becker muscular dystrophies. 5,10,11,24,28,30,31,33,36 Although deficiencies in components of the dystrophin cytoskeleton and basal lamina result in pathologic phenotypes, the primary absence of one component often leads to secondary deficiencies of other components. 4,5,31,32 This observation has led to attempts to identify single components that, when deficient, result in muscular dystrophy; however, important case studies have been reported which contradict a single factorial model in muscular dystrophy.…”