title: Contribution of novel ATGL missense mutations to the clinical phenotype of NLSD-M: a strikingly low amount of lipase activity may preserve cardiac function.
abstract: The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase domain-containing enzyme that hydrolyzes fatty acids from triacylglycerol (TAG) stored in multiple tissues, causes the autosomal recessive disorder neutral lipid storage disease with myopathy (NLSD-M). In two families of Lebanese and Italian origin presenting with NLSD-M, we identified two new missense mutations in highly conserved regions of ATGL (p.Arg221Pro and p.Asn172Lys) and a novel nonsense mutation (p.Trp8X). The Lebanese patients harbor homozygous p.Arg221Pro, whereas the Italian patients are heterozygotes for p.Asn172Lys and the p.Trp8X mutation. The p.Trp8X mutation results in a complete absence of ATGL protein, while the p.Arg221Pro and p.Asn172Lys mutations result in proteins with minimal lipolytic activity. Although these mutations did not affect putative catalytic residues or the lipid droplet (LD)-binding domain of ATGL, cytosolic LDs accumulated in cultured skin fibroblasts from the patients. The missense mutations might destabilize a random coil (p.Asn172Lys) or a helix (p.Arg221Pro) structure within or proximal to the patatin domain of the lipase, thereby interfering with the enzyme activity, while leaving intact the residues required to localize the protein to LDs. Overexpressing wild-type ATGL in one patient's fibroblasts corrected the metabolic defect and effectively reduced the number and area of cellular LDs. Despite the poor lipase activity in vitro, the Lebanese siblings have a mild myopathy and not clinically evident myocardial dysfunction. The patients of Italian origin show a late-onset and slowly progressive skeletal myopathy. These findings suggest that a small amount of correctly localized lipase activity preserves cardiac function in NLSD-M.
authors.affiliation: Laboratory of Human Molecular Biology and Genetics, Catholic University of the Sacred Heart, Milan, Italy. daniela.tavia@unicatt.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Tavian
authors.forename: Sara
authors.initials: S
authors.lastname: Missaglia
authors.forename: Chiara
authors.initials: C
authors.lastname: Redaelli
authors.forename: Elena M
authors.initials: EM
authors.lastname: Pennisi
authors.forename: Gloria
authors.initials: G
authors.lastname: Invernici
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wessalowski
authors.forename: Robert
authors.initials: R
authors.lastname: Maiwald
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D008049:Lipase; D014280:Triglycerides; C494794:PNPLA2 protein, human; D000217:Acyltransferases