LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.
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.
Michot
Caroline
C
Paris Descartes University, INSERM U781 and Ref Center of Metabolic Diseases, Necker Hospital, Paris, France.
Hubert
Laurence
L
Brivet
Michèle
M
De Meirleir
Linda
L
Valayannopoulos
Vassili
V
Müller-Felber
Wolfgang
W
Venkateswaran
Ramesh
R
Ogier
Hélène
H
Desguerre
Isabelle
I
Altuzarra
Cécilia
C
Thompson
Elizabeth
E
Smitka
Martin
M
Huebner
Angela
A
Husson
Marie
M
Horvath
Rita
R
Chinnery
Patrick
P
Vaz
Frederic M
FM
Munnich
Arnold
A
Elpeleg
Orly
O
Delahodde
Agnès
A
de Keyzer
Yves
Y
de Lonlay
Pascale
P
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
D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C485999:LPIN1 protein, human; C079831:PAH1 protein, S cerevisiae; D010711:Phosphatidate Phosphatase