LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

Caroline Michot (1, 2) , Laurence Hubert (1) , Michele Brivet (3) , Linda de Meirleir (4) , Vassili Valayannopoulos (5) , Wolfgang Müller-Felber (6) , Ramesh Venkateswaran (7) , Helene Ogier de Baulny (8) , Isabelle Desguerre (5) , Cécilia Altuzarra (9) , Elizabeth Thompson (10) , Martin Smitka (11) , Angela Hübner (11) , Marie Husson (12) , Rita Horvath (13) , Patrick Chinnery (14) , Frederic M Vaz (15) , Arnold Munnich (1) , Orly Elpeleg (16) , Agnès Delahodde (17) , Yves de Keyser (1) , Pascale de Lonlay (1, 5, 18)

1 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
2 Metabolic Diseases
3 biochemistry
4 Pediatric neurology- metabolic diseases
5 Department of Neuro-Metabolism
6 Department of Pediatrics
7 Pediatrics
8 pediatric metabolic unit
9 Pediatrics
10 SA Clinical Genetics
11 Neuropaediatrics
12 Department of Pediatrics
13 Mitochondrial Research Group, Institute for Aging and Health
14 Mitochondrial Research Group
15 Department of Clinical Chemistry
16 Hadassah Medical Center
17 IGM - Institut de génétique et microbiologie [Orsay]
18 pediatric metabolic unit

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 ∆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.

Mots clés: Life Sciences

Caroline Michot, Laurence Hubert, Michele Brivet, Linda de Meirleir, Vassili Valayannopoulos, et al.. LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.. Human Mutation, 2010, 31 (7), pp.E1564-73. ⟨10.1002/humu.21282⟩. ⟨hal-00552397⟩