title: LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.
abstract: Autosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement Delta pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy.
authors.affiliation: Paris Descartes University, INSERM U781 and Ref 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: Michèle
authors.initials: M
authors.lastname: Brivet
authors.forename: Linda
authors.initials: L
authors.lastname: De Meirleir
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Müller-Felber
authors.forename: Ramesh
authors.initials: R
authors.lastname: Venkateswaran
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Cécilia
authors.initials: C
authors.lastname: Altuzarra
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.forename: Martin
authors.initials: M
authors.lastname: Smitka
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Marie
authors.initials: M
authors.lastname: Husson
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Patrick
authors.initials: P
authors.lastname: Chinnery
authors.forename: Frederic M
authors.initials: FM
authors.lastname: Vaz
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
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; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D010711:Phosphatidate Phosphatase / Q000235:genetics; D012206:Rhabdomyolysis / Q000235:genetics* / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C485999:LPIN1 protein, human; C079831:PAH1 protein, S cerevisiae; D010711:Phosphatidate Phosphatase