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ABSTRACT: Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable.
Genetic variants in the promoter region of the vitamin D receptor (VDR) gene may explain the response to treatment because this receptor mediates vitamin D action.
We studied the VDR promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1alpha-hydroxyvitamin D3 derivatives and phosphates from early childhood on.
Treatment improved bone deformities and final height, but 39% of treated patients still had short stature at the end of growth (-2 sd score or below). Height was closely associated with VDR promoter Hap1 genotype. Hap1(-) patients (35% of the cohort) had severe growth defects. This disadvantageous association of Hap1(-) status with height was visible before treatment, under treatment, and on to adulthood. Gender and age at initiation of treatment could not account for the Hap1 effect. No association with growth was found with a polymorphism of the PTH receptor gene otherwise found to be associated with adult height. Compared with Hap1(+) patients, those who were Hap1(-) had a higher urinary calcium response to 1alpha-hydroxyvitamin D3 and had significantly lower circulating FGF23 levels (C-terminal assay), taking into account their phosphate and 1alpha-hydroxyvitamin D3 intakes.
The present work identifies the VDR promoter genotype as a key predictor of growth under treatment with 1alpha-hydroxyvitamin D3 derivatives in patients with hypophosphatemic rickets, including those with established PHEX alterations. The VDR promoter genotype appears to provide valuable information for adjusting treatment and for deciding upon the utility of early GH therapy.
Journal of Clinical Endocrinology & Metabolism 10/2008; 93(12):4672-82. · 6.50 Impact Factor
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ABSTRACT: We describe a mutation in human erythrocyte band 3 (anion exchanger 1; SLC4A1) causing both hereditary spherocytosis and distal renal tubular acidosis. The proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype; other proteins of the band 3/Rh macrocomplex were also reduced. DNA sequence analysis revealed a novel homozygous mutation, c.2000C>T, leading to the amino acid substitution Ser667Phe. The parents were heterozygous for the same mutation. Sulfate influx in the patient's erythrocytes was approximately 40% wild type. The mutant band 3 produced very little chloride influx when expressed in Xenopus oocytes. Influx was partially rescued by coexpression of glycophorin A and also rescued by coexpression of wild-type band 3. At 2 years of age, an ammonium chloride challenge showed the child has incomplete distal renal tubular acidosis (dRTA). Stable expression of mutant kidney band 3 in both nonpolarized and polarized Madin-Darby canine kidney cells showed that most of the mutant protein was retained in the endoplasmic reticulum. Overall our results suggest that the Ser667Phe does not affect the anion transport function of band 3, but causes a trafficking defect in both erythrocytes and kidney cells.
Blood 06/2008; 111(11):5380-9. · 9.90 Impact Factor
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Rosa Vargas-Poussou,
Pascal Houillier,
Nelly Le Pottier,
Laurence Strompf,
Chantal Loirat,
Véronique Baudouin,
Marie-Alice Macher, Michèle Déchaux,
Tim Ulinski,
François Nobili, [......],
Ivan Tack,
Anne Fargeot,
François Bouissou,
Gwenaelle Roussey Kesler,
Stéphanie Lorotte,
Nathalie Godefroid,
Valérie Layet,
Gilles Morin,
Xavier Jeunemaître,
Anne Blanchard
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ABSTRACT: Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.
Journal of the American Society of Nephrology 06/2006; 17(5):1437-43. · 9.66 Impact Factor
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ABSTRACT: The extracellular Ca(2+)-sensing receptor (CaSR) plays an essential role in extracellular Ca(2+) homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaCl transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaCl reabsorption with renal loss of NaCl has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca(2+) and ERK activity, showed a dramatic reduction in the EC(50) for extracellular Ca(2+) compared with the wild-type and a loss-of-function mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaCl reabsorption in the cTAL sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.
Journal of the American Society of Nephrology 10/2002; 13(9):2259-66. · 9.66 Impact Factor
