ABSTRACT
Neutral lipid storage disease with myopathy (NLSDM) referred to those neutral lipid storage disease (NLSD) patients with myopathy but without ichthyosis. Recently, NLSDM has been attributed to mutations in the PNPLA2 gene. Until now, 19 patients with PNPLA2 mutations have been reported. In the present study, we describe the clinical and genetic findings in three Chinese patients with NLSDM. Sequence analysis of PNPLA2 gene was performed. In our patients we identified four novel mutations in the PNPLA2 gene including two splicing mutations. The identification and study of mutations found in PNPLA2 is also particularly important to define the clinical spectrum and genotype-phenotype correlations of the PNPLA2 gene.
Subject(s)
Asian People/genetics , Lipase/genetics , Lipid Metabolism, Inborn Errors/genetics , Muscular Diseases/genetics , Mutation , Adult , Biopsy , DNA Mutational Analysis , Female , Genetic Association Studies , Humans , Lipid Metabolism, Inborn Errors/pathology , Male , Middle Aged , Muscles/pathology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Muscular Diseases/pathology , Population Groups/geneticsABSTRACT
Skeletal muscle weakness is a reported ailment in individuals working in commercial hog confinement facilities. To date, specific mechanisms responsible for this symptom remain undefined. The purpose of this study was to assess whether hog barn dust (HBD) contains components that are capable of binding to and modulating the activity of type 1 ryanodine receptor Ca2+-release channel (RyR1), a key regulator of skeletal muscle function. HBD collected from confinement facilities in Nebraska were extracted with chloroform, filtered, and rotary evaporated to dryness. Residues were resuspended in hexane-chloroform (20:1) and precipitates, referred to as HBDorg, were air-dried and studied further. In competition assays, HBDorg dose-dependently displaced [3H]ryanodine from binding sites on RyR1 with an IC50 of 1.5±0.1 microg/ml (Ki=0.4±0.0 microg/ml). In single-channel assays using RyR1 reconstituted into a lipid bilayer, HBDorg exhibited three distinct dose-dependent effects: first it increased the open probability of RyR1 by increasing its gating frequency and dwell time in the open state, then it induced a state of reduced conductance (55% of maximum) that was more likely to occur and persist at positive holding potentials, and finally it irreversibly closed RyR1. In differentiated C2C12 myotubes, addition of HBD triggered a rise in intracellular Ca2+ that was blocked by pretreatment with ryanodine. Since persistent activation and/or closure of RyR1 results in skeletal muscle weakness, these new data suggest that HBD is responsible, at least in part, for the muscle ailment reported by hog confinement workers.