Characterization of the Gene Encoding Human Sarcolipin (SLN), a Proteolipid Associated with SERCA1: Absence of Structural Mutations in Five Patients with Brody Disease

Sarcolipin (SLN) is a low-molecular-weight protein that copurifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ATPase (SERCA1). Genomic DNA and cDNA encoding human sarcolipin (SLN) were isolated and characterized and theSLNgene was mapped to chromosome 11q22–q23. Human, rabbit, and mouse cDNAs encode a protein of 31 amino acids. Homology of SLN with phospholamban (PLN) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amino acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are lumenal. The cytoplasmic and transmembrane sequences are not well conserved among the three species, but the lumenal sequence is highly conserved. Like SERCA1, SLN is highly expressed in rabbit fast-twitch skeletal muscle, but it is expressed to a lower extent in slow-twitch muscle and to an even lower extent in cardiac muscle, where SERCA2a and PLN are highly expressed. It is expressed in only trace amounts in pancreas and prostate.SLNandPLNgenes resemble each other in having two small exons, with their entire coding sequences lying in exon 2 and a large intron separating the two segments. Brody disease is an inherited disorder of skeletal muscle function, characterized by exercise-induced impairment of muscle relaxation. Mutations in theATP2A1gene encoding SERCA1 have been associated with the autosomal recessive inheritance of Brody disease in three families, but not with autosomal dominant inheritance of the disease. A search for mutations in theSLNgene in five Brody families, four of which were not linked toATP2A1,did not reveal any alterations in coding, splice junction or promoter sequences. The homozygous deletion of C438 in the coding sequence ofATP2A1in Brody disease family 3, leading to a frameshift and truncation following Pro147in SERCA1, is the fourthATP2A1mutation to be associated with autosomal recessive Brody disease.