A new evidence for the maintenance of the sarcoglycan complex in muscle sarcolemma in spite of the primary absence of δ-SG protein

δ-Sarcoglycan (δ-SG) is one of the first proteins of the sarcoglycan complex (SGC) to be expressed during muscle development, and it has been considered fundamental for the assembling and insertion of the SGC in the sarcolemma. Studies using heterologous cell systems and co-precipitation have demonstrated that SGC assembly was dependent on the simultaneous synthesis of all four sarcoglycan proteins. Mutations in any one of sarcoglycan genes, including the common disease causing mutation c.656delC in the δ-SG gene, block complex formation and its insertion in the plasma membrane. Failure in complex assembly in patients with this mutation would be therefore expected. In this study, we provide evidence for the possibility of preservation of part of the SG complex in the sarcolemma, even in the absence of δ-SG. This is based on the study of one mildly affected patient with limb-girdle muscular dystrophy type 2F (LGMD2F) due to the homozygous c.656delC mutation in the δ-SG gene. Protein analysis in his muscle biopsy presented a significant deficiency of only δ-SG with retention of the other three SG proteins in the sarcolemma. RNA expression analysis showed that ζ-SG, a functionally homologous to δ-SG, is not atypically upregulated in his muscle and would not replace the absent δ-SG, retaining the complex α−β−γ−ζ. The patient started clinical manifestation at age 25, with frequent falls, but he is currently able to walk unassisted at age 42. His clinical course is significantly milder when compared to several other affected patients carrying the same mutation associated with a total deficiency of the four SG proteins in the muscle studied by our group and confirmed in other patients. Therefore, our results add a new in vivo evidence that α-, β-, and γ-SG proteins can be maintained in the sarcolemma without δ-SG. Additionally, LGMD2F, with retention of the part of the SGC, might be associated to a milder clinical course, which has important implications for clinical prognosis and genetic counseling of the family.