CHARACTERIZATION OF THE GENE ENCODING HUMAN SARCOLIPIN (SLN), A PROTEOLIPID ASSOCIATED WITH SERCA1 - ABSENCE OF STRUCTURAL MUTATIONS IN 5 PATIENTS WITH BRODY-DISEASE

Sarcolipin (SLN) is a low-molecular-weight protein that copurifies wit h the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase ( SERCA1), Genomic DNA and cDNA encoding human sarcolipin (SLN) were iso lated and characterized and the SLN gene was mapped to chromosome 11q2 2-q23, Human, rabbit, and mouse cDNAs encode a protein of 31 amino aci ds. Homology of SLN with phospholamban (PLN) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amin o acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are lumenal, The cytoplasmic and transmembrane sequences a re not well conserved among the three species, but the lumenal sequenc e 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, wher e SERCA2a and PLN are highly expressed, It is expressed in only trace amounts in pancreas and prostate, SLN and PLN genes resemble each othe r in having two small exons, with their entire coding sequences lying in exon 2 and a large intron separating the two segments, Brody diseas e is an inherited disorder of skeletal muscle function, characterized by exercise-induced impairment of muscle relaxation. Mutations in the ATP2A1 gene encoding SERCA1 have been associated with the autosomal re cessive inheritance of Brody disease in three families, but not with a utosomal dominant inheritance of the disease, A search for mutations i n the SLN gene in five Brody families, four of which were not linked t o ATP2A1, did not reveal any alterations in coding, splice junction or promoter sequences, The homozygous deletion of C438 in the coding seq uence of ATP2A1 in Brody disease family 3, leading to a frameshift and truncation following Pro(147) in SERCA1, is the fourth ATP2A1 mutatio n to be associated with autosomal recessive Brody disease. (C) 1997 Ac ademic Press.