Fragile X mental retardation syndrome is caused by the unstable expansion of a CGG repeat in the FMR-1 gene. In patients with a full mutation, abnormal methylation results in suppression of FMR-1 transcription. FMR-1 is expressed in many tissues but its function is unknown. We have raised monoclonal antibodies specific for the FMR-1 protein. They detect 4-5 protein bands which appear identical in cells of normal males and of males carrying a premutation, but are absent in affected males with a full mutation. Immunohistochemistry shows a cytoplasmic localization of FMR-1. The highest levels were observed in neurons, while glial cells contain very low levels. In epithelial tissues, levels of FMR-1 were higher in dividing layers. In adult testis, FMR-1 was detected only in spermatogonia. FMR-1 was not detected in dermis and cardiac muscle except under pathological conditions.
Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.
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