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Case Reports
. 2008 Oct;83(4):489-94.
doi: 10.1016/j.ajhg.2008.09.002. Epub 2008 Sep 25.

Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood

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Free PMC article
Case Reports

Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood

Avraham Zeharia et al. Am J Hum Genet. .
Free PMC article

Erratum in

  • Am J Hum Genet. 2009 Jan;84(1):95

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.

Figures

Figure 1
Figure 1
The Family Pedigree and the Haplotypes along the Critical Region on Chromosome 2 Patients' symbols are filled. Numbered symbols represent individuals whose DNA samples were available for analysis. The polymorphic microsatellite markers and their chromosomal locations (in Mb) are given in the upper left panel. Only siblings whose DNA samples were available were included in this figure.
Figure 2
Figure 2
Patient 2572, Age 10 Years Note Normal Fat Distribution
Figure 3
Figure 3
Triacylglycerol and Phospholipid Biosynthetic Pathway Abbreviations are as follows: AGPAT, 1-acyl-sn-glycero-3-phosphate acyltransferase; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; Glycerol-3-P, glycerol-3-phosphate; LPC, lyso-phosphatidylcholine; LPE, lyso-phosphatidylethanolamine; PLA2, phospholipase A2; LPEAT, lysophosphatidylethanolamine acyltransferase; LPCAT, lysophosphatidylcholine acyltransferase; LIPIN, phosphatidic acid phosphatase; MLCL, Monolyso-cardiolipin; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI(4,5)P2, phosphatidylinositol 4,5-diphosphate; TAG, triacylglycerol; TAZ, 1-palmitoyl-2-linoleoyl-phosphatidylcholine:monolysocardiolipin linoleoyltransferase.
Figure 4
Figure 4
Human LPIN1 but Not LPIN1- E769G Can Partially Complement a Δpah1 Yeast Strain Wild-type (WT-W303) and Δ pah1 strains harboring an empty plasmid (Yep51) or plasmids encoding derivatives of the normal human LPIN1 (YEp-LPIN1), the mutant human LPIN1 (YEp-E769G or Yep-P610S) or the normal yeast PAH1 (pGH316) were grown overnight at 30°C in glucose medium. Cultures at a density of 4 × 107 cells/ml were serially diluted at 10-fold intervals (numbered 1, 2, 3 and 4 for 101, 102, 103 and 104 dilutions, respectively) and 10 μl of each was spotted onto plates containing 2% glucose or 2% glycerol. The cells on glucose and glycerol medium were incubated at 30°C for 3 and 7 days, respectively.

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