Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia

Caroline Michot, Laurence Hubert, Norma B. Romero, Amr Gouda, Asmaa Mamoune, Suja Mathew, Edwin Kirk, Louis Viollet, Shamima Rahman, Soumeya Bekri, Heidi Peters, James McGill, Emma Glamuzina, Michelle Farrar, Maya Von Der Hagen, Ian E. Alexander, Brian Kirmse, Magalie Barth, Pascal Laforet, Pascale BenlianArnold Munnich, Marc Jeanpierre, Orly Elpeleg, Ophry Pines, Agnès Delahodde, Yves De Keyzer, Pascale De Lonlay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Background: Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. Methods: Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. Results: Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. Conclusion: LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations.

Original languageAmerican English
Pages (from-to)1119-1128
Number of pages10
JournalJournal of Inherited Metabolic Disease
Issue number6
StatePublished - Nov 2012

Bibliographical note

Funding Information:
Acknowledgements We thank all physicians who referred us the DNA samples of their patients. We thank Mai Thao Viou for the muscle histochemistry and electron microscopy, and Caroline Rambaud for the results of autopsy. This work was supported by Association Française contre les Myopathies [grant n° 13988] and Fondation de l’Avenir [grant n°09071] to Pr De Lonlay. Caroline Michot was supported by the Fon-dation pour la Recherche Médicale and by INSERM (poste d’accueil INSERM).


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