Résumé :
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Introduction: Main metabolic causes of myopathies are fatty acid oxidation (FAO) deficiencies. LPIN1 defects have been involved in severe and early rhabdomyolysis. Lipin1 plays a dual role, as a phosphatidate phosphatase 1 (PAP1) and as a transcriptionnal coactivator of PPAR and PGC1 to regulate the expression of many genes, including those encoding FAO enzymes. The human Lipin family includes two other closely related members, Lipin 2 and 3, encoded by distinct genes. All three Lipin exhibit PAP1 activity and possess the LxxIL motif mediating interaction with nuclear factors.The aim of the study is to evaluate the prevalence of LPIN1, LPIN2 and LPIN3 mutations in a cohort of patients presenting with a wide spectrum of muscular diseases. Methods: 117 patients were recruited. Inclusion criteria were rhabdomyolysis bouts or exercice-induced muscular pains, in children or adults, after exclusion of FAO deficiency. The complete coding sequences of the three genes were analysed. Functional consequences of the substitutions were evaluated by a complementation test in the pah1 yeast strain. Results: We found 2 LPIN1 mutations in 22 patients (19%), 1 LPIN1 substitution in 1 patient, 1 LPIN2 substitution in 4 patients and 1 LPIN3 substitution in 4 patients. No patient was found with 2 mutations in LPIN2 or LPIN3.All patients with 2 LPIN1 mutations presented with severe (CPK > 10 000 UI/L) and early (first bout < 7 years) episodes of rhabdomyolysis. A triggering factor was noted in most cases, mostly fever. 7/22 patients (32%) died during one episode from cardiac arrest (hyperkalemia). 12/13 mutations were stops or frameshifts mutations. 1 in-frame intragenic deletion, functionally less active, was found in 11/22 patients, all Caucasians (funding effect). Between bouts, patients had normal physical examination and CK except two. Moderate excess of lipid droplets was observed in muscle of most patients. Some parents or heterozygous siblings were symptomatic (cramps, weakness).All 9 patients with 1 substitution of LPIN1, 2 or 3 presented with late or moderate rhabdomyolysis or muscular pain. The variants were inherited from healthy parents, and resulted in the change of a conserved amino acid, not found in 250 control alleles. The LPIN1, LPIN2 and LPIN3 complementation tests showed variable impact of these variants.Discussion and conclusion: Recessive LPIN1 mutations are observed only in severe and early episodes of rhabdomyolysis (48% of severe patients). Heterozygous LPIN1, 2 or 3 substitutions are found in a few patients with milder muscular phenotypes. The relationship between these variants and the diseases remains an open question. Our reports underline the importance of a tight surveillance of the myolysis bouts. This work was done with the help of AFM.
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