Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome.
Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored. They are all forms of the renal Fanconi syndrome and are associated with tubular proteinuria. Urine samples of equal creatinine contents were dialyzed, lyophilized, and subjected to electrophoresis on nonreducing sodium dodecyl sulfate-5% polyacrylamide gels. Proteins were blotted and probed with anti-megalin IgG, anti-cubilin IgG, or receptor-associated protein. Megalin and cubilin levels detected by immunochemiluminescence were measured as integrated pixels and expressed as percentages of the normal mean values. A striking deficiency of urinary megalin, compared with normal individuals (n = 42), was observed for eight of nine families with Dent's disease (n = 10) and for the two families with Lowe's syndrome (n = 3). The family with autosomal dominant idiopathic Fanconi syndrome (n = 2) exhibited megalin levels within the normal range. The measured levels of cubilin were normal for all patients. These results are consistent with defective recycling of megalin to the apical cell surface of the proximal tubules and thus decreased loss into urine in Dent's disease and Lowe's syndrome. This defect would interfere with the normal endocytic function of megalin, result in losses of potential ligands into the urine, and produce tubular proteinuria.
Norden
Anthony G W
AGW
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Lapsley
Marta
M
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Igarashi
Takashi
T
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Kelleher
Catherine L
CL
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Lee
Philip J
PJ
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Matsuyama
Takeshi
T
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Scheinman
Steven J
SJ
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Shiraga
Hiroshi
H
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Sundin
David P
DP
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Thakker
Rajesh V
RV
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Unwin
Robert J
RJ
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Verroust
Pierre
P
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Moestrup
Søren K
SK
*Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Chemical Pathology, Epsom and St. Helier Trust, Epsom, United Kingdom; Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Division on Aging and Department of Genetics, Harvard Medical School, Boston, Massachusetts; Charles Dent Metabolic Unit and Centre for Nephrology, University College London Hospitals, London, United Kingdom; Department of Pediatrics, Fussa Hospital, Tokyo, Japan; Department of Medicine, State University of New York, Syracuse, New York; **Department of Paediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan; Division of Nephrology, Indianapolis School of Medicine, Indianapolis, Indiana; Molecular Endocrinology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom; INSERM U 538, Paris, France; and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
D004705:Endocytosis; D005198:Fanconi Syndrome / Q000503:physiopathology* / Q000652:urine; D006801:Humans; D007684:Kidney Tubules / Q000503:physiopathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency*; D008297:Male; D009800:Oculocerebrorenal Syndrome / Q000503:physiopathology / Q000652:urine; D012016:Reference Values; D014556:Urine / Q000737:chemistry
D026561:Low Density Lipoprotein Receptor-Related Protein-2