The sarcoglycan complex in the six autosomal recessive limb-girdle muscular dystrophies

Abstract

To enhance our understanding of the autosomal recessive limb-girdle muscular dystrophy (LGMD), patients from six genetically distinct forms (LGMD2A to LGMD2F) were studied with antibodies directed against four sarcoglycan subunits (alpha-, beta-, gamma-, delta-SG), dystrophin, beta-dystroglycan (beta-DG) and merosin. All patients with LGMD2A and 2B had a mild clinical course while those with a primary sarcoglycan mutation (LGMD2C to 2F) had a range of clinical severity. Dystrophin and merosin immunofluorescence pattern was positive in patients with all six AR LGMDs. The majority of patients with a severe Duchenne-like phenotype presented total absence of the SG complex. However, some exceptions were found in 13q linked patients, indicating that the presence of a certain labelling for components of the SG may not be prognostic for a milder phenotype. The observation that the primary absence of alpha-SG results in the total absence of beta- and delta-SG but not of gamma-SG suggests that the alpha-, beta- and delta-subunits of sarcoglycan may be more closely associated. A secondary reduction in dystrophin amount was seen in patients with primary sarcoglycan mutations, which was most marked in patients with primary beta-, gamma- and delta-SG deficiencies. In contrast, beta-DG staining was retained in all patients, suggesting that the association between SG and DG subcomplexes is not so strong. Based on the above findings, we have refined the model for the interaction among the known glycoproteins of the sarcoglycan complex, within the DGC.

Further evidence for the organisation of the four sarcoglycans proteins within the dystrophin–glycoprotein complex

“…Based on the above findings, we have suggested that α, and δ subunits of sarcoglycan might be more closely associated, whilst γ-SG might interact more directly with dystrophin. 12 Here we report two additional SGpathy patients with a 'DMD-like presentation' which gives further support to our previous study. In addition, one of them illustrates the potential risk of misdiagnosis in cases with a patchy pattern of dystrophin by means of IF methodology.…”

Protein defects in neuromuscular diseases

“…In most muscle biopsies from patients with a primary sarcoglycanopathy, the primary loss or deficiency of any one of the four SG, ß-SG and d-SG in particular, leads to a secondary deficiency of the whole subcomplex ( Figure 3) (3,4,26,36,37). However, exceptions may occur, such as the deficiency of g-SG with a partial preservation of the other three SG in LGMD2C (37) or the partial deficiency of only a-SG with the retention of the other three in LGMD2D (36,38).…”

“…However, exceptions may occur, such as the deficiency of g-SG with a partial preservation of the other three SG in LGMD2C (37) or the partial deficiency of only a-SG with the retention of the other three in LGMD2D (36,38). The observation of a complete deficiency of one SG with partial deficiency of the others may help to indicate which gene should be first screened for mutations.…”

“…This suggests that g-SG might interact more directly with dystrophin (37). Therefore, a relative dystrophin deficiency may occur in non-BMD, and this should be taken into consideration for differential diagnosis.…”

A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21

“…Routine histological and histochemical analysis include staining for hematoxylin and eosin (H&E), modified Gomori trichrome, SDH, NADH, acid phosphatases, and ATPase at pH 9.4 and 4.3 15 Proteins analysis were performed through immunofluorescence (IF) and Western blot (WB) methodologies, as previously described. 16,17 The following antibodies were used: dystrophin, 18 sarcoglycans a, b, g and d, 19 calpain-3, 20 , dysferlin 21 and telethonin. 22 Microsatellite marker analysis DNA was isolated from blood by standard methods.…”