title: Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.
abstract: Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis. The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis. Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene. Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype. Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy.
authors.affiliation: The Metabolic Disease Unit, Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.forename: Tareq
authors.initials: T
authors.lastname: Hindi
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Gilli
authors.initials: G
authors.lastname: Erez
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Yves
authors.initials: Y
authors.lastname: de Keyzer
authors.forename: Gideon
authors.initials: G
authors.lastname: Eshel
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.forename: Ophry
authors.initials: O
authors.lastname: Pines
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D002648:Child; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008954:Models, Biological; D008957:Models, Genetic; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D009212:Myoglobinuria / Q000175:diagnosis* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010711:Phosphatidate Phosphatase; D012206:Rhabdomyolysis / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase