Abstract
Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from animal models suggest that sodium-hydrogen exchanger regulatory factor 1 (NHERF1) controls renal phosphate transport. We sequenced the NHERF1 gene in 158 patients, 94 of whom had either nephrolithiasis or bone demineralization. We identified three distinct mutations in seven patients with a low TmP/GFR value. No patients with normal TmP/GFR values had mutations. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. These NHERF1 mutations suggest a previously unrecognized cause of renal phosphate loss in humans.
2008 Massachusetts Medical Society
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Biological Transport / genetics
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Bone Demineralization, Pathologic / genetics*
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Bone Demineralization, Pathologic / metabolism
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Bone Demineralization, Pathologic / physiopathology
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Cells, Cultured
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Cyclic AMP / biosynthesis
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Cyclic AMP / urine
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DNA Mutational Analysis
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Female
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Glomerular Filtration Rate / genetics
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Humans
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Hypercalciuria / genetics
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Kidney / cytology
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Kidney / metabolism
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Kidney Calculi / genetics*
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Kidney Calculi / metabolism
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Kidney Calculi / physiopathology
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Male
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Middle Aged
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Mutation
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Mutation, Missense
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Nephrolithiasis / genetics*
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Nephrolithiasis / metabolism
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Opossums
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Parathyroid Hormone / blood
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Parathyroid Hormone / metabolism*
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Phosphates / blood
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Phosphates / metabolism*
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Phosphoproteins / genetics*
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Sodium-Hydrogen Exchangers / genetics*
Substances
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Parathyroid Hormone
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Phosphates
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Phosphoproteins
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Sodium-Hydrogen Exchangers
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sodium-hydrogen exchanger regulatory factor
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Cyclic AMP