Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A. Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated with Fabry disease.
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PMID:Renal pathological changes in Fabry disease. 1175 81

The endocytic receptors megalin and cubilin are highly expressed in the early parts of the endocytic apparatus of the renal proximal tubule. The two receptors appear to be responsible for the tubular clearance of most proteins filtered in the glomeruli. Since cubilin is a peripheral membrane protein it has no endocytosis signaling sequence. Cubilin binds to megalin and it appears that megalin is responsible for internalization of cubilin and its ligands, in addition to internalizing its own ligands. The importance of the receptors is underscored by the proteinuria observed in megalin-deficient mice, in dogs lacking functional cubilin, and in patients with distinct mutations of the cubilin gene. In this review we focus on the role of megalin- and cubilin-mediated endocytosis in renal pathophysiology. Association between disorders characterized by tubular proteinuria, such as megaloblastic anemia type-1, Dent disease, cystinosis, and Fabry disease and the dysfunction of proximal tubular endocytosis is discussed. The correlation between the high capacity of endocytosis in the proximal tubule and progressive renal disease in overload proteinuria is considered.
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PMID:Protein reabsorption in renal proximal tubule-function and dysfunction in kidney pathophysiology. 1514 21

Deficiency of lysosomal alpha-galactosidase A (alpha-Gal A) in Fabry disease results in cellular accumulation of globotriaosylceramide (Gl3), often leading to end-stage renal failure. Gl3 accumulates in endothelial, glomerular, and tubular cells. Replacement therapy with recombinant alpha-Gal A to some extent reduces cellular accumulation of Gl3 in the kidney. This study shows high lysosomal expression of alpha-Gal A in all tubular segments and interstitial cells of normal human kidney. However, glomeruli and endothelial cells did not express the enzyme to any significant extent. Recombinant enzyme was taken up by rat yolk sac cells in a receptor-associated protein-inhibitive manner, and surface plasmon resonance experiments revealed binding to megalin, indicating a possible mechanism for uptake of alpha-Gal A in the tubular cells. After infusion into experimental animals or patients, alpha-Gal A was recovered in the urine, indicating glomerular filtration. Recombinant alpha-Gal A was also found in kidneys of normal and alpha-Gal A knockout mice by Western blotting and localized to endosomes and lysosomes in proximal tubules, interstitial cells, and glomerular podocytes by immunocytochemistry and autoradiography but not in vascular endothelial cells. In conclusion, intravenously administered enzyme is taken up by interstitial cells, is to some extent filtered in glomeruli, and is taken up by podocytes and reabsorbed by receptor-mediated endocytosis in proximal tubule cells, directly indicating a potential beneficial effect of enzyme replacement therapy for these cells.
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PMID:Distribution of alpha-galactosidase A in normal human kidney and renal accumulation and distribution of recombinant alpha-galactosidase A in Fabry mice. 1728 29