Journal of Inherited Metabolic Disease

, Volume 35, Issue 6, pp 1119–1128 | Cite as

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 Benlian
  • Arnold Munnich
  • Marc JeanPierre
  • Orly Elpeleg
  • Ophry Pines
  • Agnès Delahodde
  • Yves de Keyzer
  • Pascale de Lonlay
Original Article

Abstract

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.

Keywords

Creatine Kinase Lipid Droplet Alternative Splice Event PAP1 Activity Chronic Recurrent Multifocal Osteomyelitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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 Fondation pour la Recherche Médicale and by INSERM (poste d’accueil INSERM).

Conflict of interest

None.

Supplementary material

10545_2012_9461_MOESM1_ESM.xls (48 kb)
eTable 1 Molecular and clinical data of patients with LPIN1, LPIN2 and LPIN3 mutations or variants. The 17 previously reported patients with two LPIN1 mutations (Michot et al 2010) are shown in shaded lines. NA : not available, CK : creatine kinase. Early : patient unable to precise the beginning of his symptoms. (XLS 48 kb)

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Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Caroline Michot
    • 1
  • Laurence Hubert
    • 1
  • Norma B. Romero
    • 2
  • Amr Gouda
    • 3
  • Asmaa Mamoune
    • 1
  • Suja Mathew
    • 4
  • Edwin Kirk
    • 5
  • Louis Viollet
    • 1
  • Shamima Rahman
    • 6
    • 10
  • Soumeya Bekri
    • 7
  • Heidi Peters
    • 8
  • James McGill
    • 9
  • Emma Glamuzina
    • 10
  • Michelle Farrar
    • 11
  • Maya von der Hagen
    • 12
  • Ian E. Alexander
    • 13
  • Brian Kirmse
    • 14
  • Magalie Barth
    • 15
  • Pascal Laforet
    • 16
  • Pascale Benlian
    • 17
  • Arnold Munnich
    • 1
  • Marc JeanPierre
    • 18
  • Orly Elpeleg
    • 19
  • Ophry Pines
    • 20
  • Agnès Delahodde
    • 21
  • Yves de Keyzer
    • 1
  • Pascale de Lonlay
    • 1
    • 22
  1. 1.Paris Descartes University, INSERM U781 and Reference Center of Metabolic Diseases, Necker HospitalParisFrance
  2. 2.Pierre and Marie Curie University, UM 76, INSERM U974, CNRS UMR 7215, Neuromuscular Morphology Unit, Myology Institute, GHU Pitié-Salpêtrière, AP-HP, East-Paris Reference Center of Neuromuscular DiseasesParisFrance
  3. 3.Biochemical Genetics DepartmentNational Research CenterCairoEgypt
  4. 4.Metabolic ClinicWomen’s and Children’s HospitalAdelaideAustralia
  5. 5.Department of Medical GeneticsSydney Children’s HospitalRandwickAustralia
  6. 6.UCL Institute of Child HealthLondonUK
  7. 7.Department of Medical Biochemistry, Rouen C.H.U.RouenFrance
  8. 8.Metabolic Unit, Murdoch Children’s Research InstituteRoyal Children’s HospitalMelbourneAustralia
  9. 9.Royal Children’s HospitalHerstonAustralia
  10. 10.Metabolic MedicineGreat Ormond Street Hospital for Children NHS TrustLondonUK
  11. 11.Department of Neurology, Sydney Children’s Hospital and School of Women’s and Children’s HealthUniversity of New South WalesSydneyAustralia
  12. 12.Department of Child Neurology, Children’s HospitalTechnical University DresdenDresdenGermany
  13. 13.Genetics Metabolic Diseases ServiceThe Children’s Hospital at WestmeadSydneyAustralia
  14. 14.Genetics and MetabolismChildren’s National Medical CenterWashingtonUSA
  15. 15.Department of Medical Genetics, Angers C.H.U.AngersFrance
  16. 16.East-Paris Reference Center of Neuromuscular DiseasesG.H.U. Pitié-Salpêtrière, AP-HPParisFrance
  17. 17.Department of BiochemistryG.H.U. Saint-AntoineParisFrance
  18. 18.Department of Biochemistry and Molecular GeneticsCochin HospitalParisFrance
  19. 19.Department of Genetics and Metabolic DiseasesHadassah-Hebrew University Medical CenterJerusalemIsrael
  20. 20.Department of Microbiology and Molecular genetics, IMRIC, Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
  21. 21.Paris-Sud University, CNRS-UMR8621, Genetics and Microbiology InstituteOrsayFrance
  22. 22.Reference Center of Metabolic DiseaseParisFrance

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