title: Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Paris Descartes University, INSERM U781 and Reference Center of Metabolic Diseases, Necker Hospital, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Michot
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Amr
authors.initials: A
authors.lastname: Gouda
authors.forename: Asmaa
authors.initials: A
authors.lastname: Mamoune
authors.forename: Suja
authors.initials: S
authors.lastname: Mathew
authors.forename: Edwin
authors.initials: E
authors.lastname: Kirk
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
authors.forename: Heidi
authors.initials: H
authors.lastname: Peters
authors.forename: James
authors.initials: J
authors.lastname: McGill
authors.forename: Emma
authors.initials: E
authors.lastname: Glamuzina
authors.forename: Michelle
authors.initials: M
authors.lastname: Farrar
authors.forename: Maya
authors.initials: M
authors.lastname: von der Hagen
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
authors.forename: Brian
authors.initials: B
authors.lastname: Kirmse
authors.forename: Magalie
authors.initials: M
authors.lastname: Barth
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforet
authors.forename: Pascale
authors.initials: P
authors.lastname: Benlian
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Marc
authors.initials: M
authors.lastname: JeanPierre
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Ophry
authors.initials: O
authors.lastname: Pines
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
authors.forename: Yves
authors.initials: Y
authors.lastname: de Keyzer
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D015444:Exercise; D005260:Female; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010711:Phosphatidate Phosphatase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012206:Rhabdomyolysis / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D018076:DNA, Complementary; C502575:LPIN2 protein, human; D009687:Nuclear Proteins; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase