Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

摘要: Rhabdomyolysis is an acute syndrome due to extensive injury of skeletal muscle. Recurrent rhabdomyolysis often caused by inborn errors in intermediary metabolism, and recent work has suggested that mutations the human gene encoding lipin 1 (LPIN1) may be a common cause recurrent children. Lipin dephosphorylates phosphatidic acid form diacylglycerol (phosphatidic phosphohydrolase; PAP) acts as transcriptional regulatory protein control metabolic expression. Herein, 3-year-old boy with severe was determined compound heterozygote for novel c.1904T>C (p.Leu635Pro) substitution previously reported genomic deletion exons 18–19 (E766-S838_del) LPIN1. Western blotting patient muscle biopsy lysates demonstrated marked reduction protein, while immunohistochemical staining showed abnormal subcellular localization. We cloned cDNAs express recombinant proteins harboring pathogenic E766-S838_del allele not expressed at RNA or level. p.Leu635Pro expressed, but less stable, aggregated cytosol, targeted proteosomal degradation. Another single amino substitution, p.Arg725His, well retained its function. However, both p.Arg725His were found deficient PAP activity. Kinetic analyses loss catalysis rather than diminished substrate binding. These data suggest 1-mediated activity involved pathogenesis deficiency.