Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.
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.
Zeharia
Avraham
A
The Metabolic Disease Unit, Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
Shaag
Avraham
A
Houtkooper
Riekelt H
RH
Hindi
Tareq
T
de Lonlay
Pascale
P
Erez
Gilli
G
Hubert
Laurence
L
Saada
Ann
A
de Keyzer
Yves
Y
Eshel
Gideon
G
Vaz
Frédéric M
FM
Pines
Ophry
O
Elpeleg
Orly
O
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
D009687:Nuclear Proteins; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase