The glycosylphosphatidylinositol (GPI) anchor is a membrane attachment structure of many proteins and occurs in a wide variety of eukaryotes from yeasts to mammals. The structure of the core of the GPI anchor is conserved in protozoa and mammals and so is its biosynthetic pathway. A complementary DNA encoding a human protein termed PIG-A (phosphatidylinositol glycan-class A) was cloned. PIG-A was necessary for synthesis of N-acetylglucosaminyl-phosphatidylinositol, the very early intermediate in GPI-anchor biosynthesis.
Abstract,32-Microglobulin (#2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis, a complication of long-term hemodialysis patients. Amyloid fibril proteins were isolated from connective tissues forming carpal tunnels in hemodialysis patients with carpal tunnel syndrome. Two-dimensional polyacrylamide gel electrophoresis and Western blotting demonstrated that most of the fl2M forming amyloid fibrils exhibited a more acidic pI value than normal ,B2M. This acidic /@2M was also found in a small fraction of f2M in sera and urine from these patients, whereas heterogeneity was not observed in healthy individuals. We purified acidic and normal iB2M from the urine of long-term hemodialysis patients and compared their physicochemical and immunochemical properties. Acidic ,62M, but not normal 6l2M, was brown in color and fluoresced, both of which are characteristics of advanced glycation end products (AGEs) of the Maillard reaction. Immunochemical studies showed that acidic #2M reacted with anti-AGE antibody and also with an antibody against an Amadori product, an early product of the Maillard reaction, but normal f2M did not react with either antibody. Incubating normal I2M with glucose in vitro resulted in a shift to a more acidic pI, generation of fluorescence, and immunoreactivity to the anti-AGE antibody. The #2M forming amyloid fibrils also reacted with anti-AGE antibody. These data provided evidence that AGE-modified
Paroxysmal nocturnal haemoglobinuria (PNH), an acquired clonal blood disorder, is caused by the absence of glycosyl phosphatidylinositol (GPI)‐anchored surface proteins due to a defect in a specific step of GPI‐anchor synthesis. The cDNA of the X‐linked gene, PIG‐A, which encodes a protein required for this step has recently been isolated. We have carried out a molecular and functional analysis of the PIG‐A gene in four cell lines deficient in GPI‐linked proteins, obtained by Epstein‐Barr virus (EBV) transformation of affected B‐lymphocytes from PNH patients. In all four cell lines transfection with PIG‐A cDNA restored normal expression of GPI‐linked proteins. In three of the four cell lines the primary lesion is a frameshift mutation. In two of these there is a reduction in the amount of full‐length mRNA. The fourth cell line contains a missense mutation in PIG‐A. In each case the mutation was present in the affected granulocytes from peripheral blood of the patients, but not in normal sister cell lines from the same patient. These data prove that PNH is caused in most patients by a single mutation in the PIG‐A gene. The nature of the mutation can vary and most likely occurs on the active X‐chromosome in an early haematopoietic stem cell.
Idiopathic pulmonary fibrosis (IPF) risk-related factors were epidemiologically investigated on the basis of 1,311 Japanese IPF autopsy cases selected from the annual complications of autopsy data records in Japan during a 12-yr period. Age and sex distribution of the subjects revealed a high peak in their seventh decade with males predominating. The IPF rate was more than two times higher (p < 0.01) among subjects engaged in occupations that exposed them to dust or organic solvents compared with those in other jobs. To ascertain job characteristics, an autopsy-case control study was conducted using other annual volumes of the autopsy data records and a similar tendency was observed. Then, a live-case control study was undertaken of 86 subjects with IPF. A significantly higher odds ratio was noted among metal production workers and miners compared with healthy and hospital control subjects (1.37 and 1.34, respectively, p < 0.01), and also a significantly lower odds ratio among subjects who frequently eat fish. Taken together with results of recent in vitro studies, the intrapulmonary deposition of hazardous dusts, especially metallic dusts, appears to play at least a partial role in initiating IPF.
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