Human Molecular Genetics

Figure 4. The refined proposed model: [gamma]-SG is more intimately linked to dystrophin (although other still unknown protein (s) could mediate this interaction); [alpha]-, [beta]- and [delta]- are maintained together and may link [gamma]-SG to [beta]-DG. This model explains how a primary [alpha]-SG deficiency may be associated with a mild phenotype, as despite the consequent deficiency of [beta]-SG and [delta]-SG, the linkage between dystrophin and the basal lamina would occur through [gamma]-SG and [beta]-DG.

Some correlation between IF pattern of [alpha]-SG and the type of mutation in the [alpha]-SG gene has been previously described (22 ). Missense mutations seemed to be associated with partial presence of [alpha]-SG and a milder phenotype while null mutations were associated with the absence of [alpha]-SG and a more severe course. In our population, however, we observed that the same homozygous missense Arg77-Cys mutation may result in a mild or severe phenotype (23 ) (see also this report). Our present analysis of the components of the SG complex in muscle showed that in one severely affected patient, all four SG components were absent. However, in patients with milder phenotype, the primary deficiency of [alpha]-SG protein resulted in the total absence of [beta]-SG and [delta]-SG yet [gamma]-SG remained with a variable positive IF pattern.

We reported four families with LGMD2C and the same 521-T mutation (30 ) reported by Noguchi et al. (24 ) in Tunisian families. One family, with three affected sibs has a very mild course, in contrast to the others and those reported by Noguchi (24 ). Our present analysis of the SG complex in these patients showed a total absence of [gamma]-SG associated with a variable pattern of [alpha]-SG, [beta]-SG and [delta]-SG. In the family with a mild course, the analysis of these three components of the SG complex correlates with the clinical phenotype as the oldest affected sister, with a very mild course, had a stronger IF pattern than her two younger more severely affected sibs. However, the finding of a similar IF pattern in two unrelated and more severely affected patients (Table 1 , nos 19 and 20) argues against such a strict correlation.

An interesting point in this regard, however, is that for each patient, the pattern of staining of [alpha]-SG is similar to that seen for both [beta]-SG and [delta]-SG, that is, either all three show a weak patchy or strong patchy IF labelling.

Finally, LGMD2E and LGMD2F patients whose mutations were previously reported (29 ,31 ) had a severe DMD-like phenotype, and showed a total absence of the four components of the SG complex and a reduction in dystrophin amount.

A reduction in dystrophin quantity is not easily detected in degenerated muscles, due to the low content of muscle proteins. Most of the reported dystrophin studies on AR-LGMD patients show normal results, but based only on IF staining (22 ,24 ,26 ,37 ). In addition to the data presented here, Matsumura et al. (18 ) also described one SCARMD patient with dystrophin amount reduction. This secondary event probably greatly contributes to muscular degeneration and patients weakness in AR-LGMD.

In the sarcoglycanopathies, the analysis of dystrophin amount showed a certain correlation between deficiency of [gamma]-SG and dystrophin quantity, that is, all patients with [gamma]-SG deficiency (primary or secondary) also showed a reduction in dystrophin amount. In addition, patients with primary [alpha]-SG deficiency, who were positive for [gamma]-SG tended to show a normal amount of dystrophin suggesting a close relationship between dystrophin and [gamma]-SG. This observation is also supported by the biochemical crosslinking studies of Yoshida and Ozawa (6 ) who suggested that A4 ([gamma]-SG) may be directly associated with dystrophin. However, we cannot rule out the possibility that other still unknown protein(s) could mediate this interaction between dystrophin and [gamma]-SG. On the other hand, the presence and normal distribution of the [beta]-DG protein in patients with a total deficiency of the whole SG complex suggests that the association between these two subcomplexes may not be so strong.

In summary, the analysis of our data shows that AR-LGMD patients with a severe Duchenne-like phenotype most commonly show a total absence of the SG complex. However, one important exception is seen in 13q-linked patients, indicating that the retention of some of the SG components should not be considered prognostic for a milder phenotype. The variability in the clinical course found in patients with the same mutation, does not seem directly correlated with the primary or secondary deficiency of the proteins of the sarcoglycan complex. 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 [alpha]-, [beta]- and [delta]-SG may be more closely associated to each other than to [gamma]-SG within the DGC. Primary mutations that result in a marked decrease or absence of SG components are also associated with a decrease in dystrophin amount.

The observation that the same primary deficiency of a SG protein may lead to different secondary deficiencies of the other components of the SG complex, not necessarily related to the clinical course suggests that other factors, not directly related to the SG complex may contribute to the clinical variability in the sarcoglycanopathies. The pattern of maintenance or loss of [alpha]-, [beta]-, [gamma]- and [delta]-SG proteins in each primary SG deficiency may enhance our knowledge regarding the interaction of the different SG components within the complex.

Based on the above results, we have refined the model of interaction among the known glycoproteins of the sarcoglycan complex within the DGC (Fig. 4 ). We suggest that [alpha]-, [beta]- and [delta]-SG are more closely associated and that [gamma]-SG may more directly interact with dystrophin.

MATERIALS AND METHODS

A total of 35 (from 21 unrelated families) LGMD patients, 24 with a mild phenotype and 11 with a severe form were included in this investigation.

The diagnosis of LGMD was established through clinical examination and course of the disease, family history, serum creatine kinase levels determinations, as well as DNA and dystrophin analysis.

The degree of functional disability was assessed through Vignos scale (32 ) and motor ability tests (33 ). Patients were classified as mild LGMD when the onset of the disease occurred during the first or second decade and loss of ambulation after age 16; and severe DLMD when onset occurred in the first decade and patients were wheelchair-bound before age 16, or when the clinical course was as severe as Xp21 DMD.

Muscle samples were obtained through biceps biopsies (after informed consent), frozen in liquid nitrogen immediately after removal and stored at -70^oC until use.

Dystrophin was analyzed in all patients by IF and WB with the rabbit polyclonal N-terminal 303-8 (kindly provided by J. Chamberlain) and C-terminal monoclonal Dy8/6C5 antibodies (34 ), as described elsewhere (35 ,36 ).

The dystrophin amount on WB was estimated through densitometric analysis, using a dual-wave-length flying spot scanner, Shimadzu CS-9000. Each patient's band was compared with the adjacent normal control and corrected for the myosin content on the muscle extract viewed in the Ponceau pre-stained blot.

Immunohistochemical staining of frozen sections was done using double labelling reactions for dystrophin + [gamma]-SG, [alpha]-SG + [beta]-SG; [gamma]-SG + [delta]-SG.

The following anti-sarcoglycans antibodies were used: [alpha]-SG, monoclonal Ad1/20A6 (22 ); [beta]-SG, rabbit polyclonal antibody (31 ); [gamma]-SG, rabbit polyclonal antibody (30 ) and monoclonal 35DAG/21B5 (37 ); [delta]-SG, rabbit polyclonal raised against a glutathione S-transferase (GST)-[delta]-sarcoglycan fusion protein (28 ); [beta]-DG, monoclonal 43DAG/8D5 (38 ); Merosin, antihuman Merosin monoclonal antibody Ascites (Gibco).

The assignment of each family to a specific loci was performed through linkage analysis and screening for mutations. It was considered that a family was likely to be linked to a candidate locus if no recombinants were identified using the closest informative marker for the region tested. In families in which the maximum positive lod score was lower than 2.0, it was also verified if recombinants (or negative LOD scores) were detected with markers from the other candidate loci. The following families have been reported previously: 15q LGMD-2A (39 ,40 ); 2p LGMD-2B (40 ), 13q LGMD-2C (30 ,40 ); 17q LGMD-2D (23 ,40 ); for 4q LGMD-2E (31 ), 5q LGMD-2F (27 ,28 ).

ACKNOWLEDGMENTS

We are extremely grateful to Dr Ivo Pavanello Filho, for the procedure of muscle biopsies, to Ana Beatriz A. Vieira, for muscle and functional assessment of patients, to Cleber S. Costa, Simone Campioto, Antonia M. P. Cerqueira and Constancia Urbani for their invaluable collaboration. This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), PADCT, International Agency of Atomic Energy, Telethon- Italy, Associação Brasileira de Distrofia Muscular (ABDIM). E.M.M is supported by NIH HL03448. L.M.K. is an investigator of the Howard Hughes Medical Institute and is supported by NIH NS23740.

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