ABSTRACT
Acute decompensated Wilson's disease (WD) that presents as fulminant hepatic failure carries significant mortality without hepatic replacement. The abnormal gene implicated in WD, ATP7B, has been mapped to chromosome 13, and leads to decreased passage of copper from hepatocytes to bile. Excess copper accumulation exceeds hepatocyte storage capacity resulting in intracellular necrosis, apoptosis and cell death in various organs of the body. The hepatic injury induced by the abnormal accumulation of copper in WD has variable presentation such as acute hepatitis, rapid hepatic deterioration resembling fulminant hepatic failure, or as progressive chronic liver disease in the form of chronic active hepatitis or cirrhosis. There are reports in the literature describing monozygotic (identical) twins with similar hepatic progression requiring liver transplantation, however, with different neurological outcome after transplant. We report a case of one monozygotic twin presenting with acute liver failure requiring emergent liver transplantation while the other twin presented with mild liver disease, when both shared an identical genetic mutation.
Subject(s)
Hepatolenticular Degeneration , Liver Diseases/surgery , Liver Transplantation , Mutation , Twins, Monozygotic/genetics , Acute Disease , Adolescent , Chromosomes, Human, Pair 13/metabolism , Copper/metabolism , Disease Progression , Female , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/metabolism , Hepatolenticular Degeneration/surgery , Humans , Liver/metabolism , Liver/surgery , Liver Diseases/genetics , Liver Diseases/metabolism , Liver Failure, Acute/genetics , Liver Failure, Acute/metabolism , Liver Failure, Acute/surgeryABSTRACT
The nuclear factor of activated T cells (NFAT) family of transcription factors regulates the development and differentiation of several tissue types. Here, we examine the role of NFATC2 in skeletal muscle by analyzing adult NFATC2(-/)- mice. These mice exhibit reduced muscle size due to a decrease in myofiber cross-sectional area, suggesting that growth is blunted. Muscle growth was examined during regeneration after injury, wherein NFATC2-null myofibers form normally but display impaired growth. The growth defect is intrinsic to muscle cells, since the lack of NFATC2 in primary muscle cultures results in reduced cell size and myonuclear number in myotubes. Retroviral-mediated expression of NFATC2 in the mutant cells rescues this cellular phenotype. Myonuclear number is similarly decreased in NFATC2(-/)- mice. Taken together, these results implicate a novel role for NFATC2 in skeletal muscle growth. We demonstrate that during growth of multinucleated muscle cells, myoblasts initially fuse to form myotubes with a limited number of nuclei and that subsequent nuclear addition and increases in myotube size are controlled by a molecular pathway regulated by NFATC2.
Subject(s)
Cell Nucleus/metabolism , DNA-Binding Proteins/metabolism , Muscle Fibers, Skeletal/cytology , Muscle, Skeletal/cytology , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Animals , Blotting, Northern , Cells, Cultured , DNA-Binding Proteins/genetics , Male , Mice , Mice, Knockout , Models, Biological , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/physiology , Myogenin/metabolism , Myosin Heavy Chains/metabolism , NFATC Transcription Factors , Nuclear Proteins/genetics , Regeneration/physiology , Retroviridae/genetics , Retroviridae/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription Factors/geneticsABSTRACT
Signal transduction pathways involving calcineurin and its downstream effector NFAT have been implicated in regulating myogenesis. Several isoforms of NFAT exist that may differentially contribute to regulating skeletal muscle physiology. The purpose of this study was to determine the role of the NFATC3 isoform in skeletal muscle development. Adult mice lacking NFATC3 have reduced muscle mass compared to control mice. The smaller size of the muscles is not due to atrophy or blunted myofiber growth, but rather to a reduced number of myofibers. This reduction in myofiber number is not limited to a specific fiber type nor are the proportions of fiber types altered. The lower fiber number found in the adult NFATC3(-/-) mice is a consequence of impaired muscle development during embryogenesis. Immunohistochemical studies of E15 EDL muscles indicate that the total number of primary myofibers is decreased in NFATC3(-/-) embryos. At E17.5 no further decrease in primary myofiber number occurs; the size and organization of the myofibers are unaltered, and secondary myogenesis proceeds normally, suggesting a role for NFATC3 during early events in primary myogenesis. These results suggest a heretofore unknown role for the transcription factor NFAT in early skeletal muscle development.
