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ABSTRACT: GNAS (guanine nucleotide-binding protein, α stimulating) is a complex imprinted locus coding, besides the α-stimulatory subunit of the G protein, the paternally (extra-large, antisense and A/B) and maternally (neuroendocrine secretory protein) transcripts. Heterozygous mutations in the coding sequence of GNAS produce dominant phenotypes (combination of resistances to hormones signaling through G-protein-coupled receptors, osteodystrophy and obesity) that depend on the parental origin of the mutated allele. Likewise, alterations in the methylation at promoters of GNAS transcripts, associated or not with deletions of imprinting control regions in the nearby STX16 gene or within GNAS, prompt resistance to parathormone when affecting the maternal allele. Therefore, imprinting of GNAS is the determining factor for the variability of the phenotype. Knowledge of the various phenotypes is necessary for genetic counseling as well as an appropriate therapeutic balance between regular follow-up, prevention of disease complications and iatrogeny.
Hormone Research in Paediatrics 03/2013;
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ABSTRACT: Hypoparathyroidism in children is most often due to mutations in genes involved in parathyroid development and calcium homeostasis signaling. Some rare cases result from autoimmune attack on the parathyroid glands as a part of the type 1 polyglandular failure syndrome (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). The majority of cases of pediatric hypoparathyroidism are well controlled under conventional treatment with calcium and vitamin D analogs. However, this treatment may be difficult to manage, especially in two situations: 1) in the context of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and 2) activating mutations in the calcium-sensing receptor. We successfully treated three patients with hypoparathyroidism with continuous subcutaneous administration of rhPTH(1-34) (recombinant human PTH(1-34)), two of which were refractory to conventional therapy.
The Journal of clinical endocrinology and metabolism 08/2011; 96(11):3308-12. · 6.50 Impact Factor
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Agnès Linglart,
Christine Menguy,
Alain Couvineau,
Colette Auzan,
Yasemin Gunes,
Mathilde Cancel,
Emmanuelle Motte,
Graziella Pinto,
Philippe Chanson,
Pierre Bougnères,
Eric Clauser, Caroline Silve
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ABSTRACT: The skeletal dysplasia characteristic of acrodysostosis resembles the Albright's hereditary osteodystrophy seen in patients with pseudohypoparathyroidism type 1a, but defects in the α-stimulatory subunit of the G-protein (GNAS), the cause of pseudohypoparathyroidism type 1a, are not present in patients with acrodysostosis. We report a germ-line mutation in the gene encoding PRKAR1A, the cyclic AMP (cAMP)-dependent regulatory subunit of protein kinase A, in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated subunit impairs the protein kinase A response to stimulation by cAMP; this explains our patients' hormone resistance and the similarities of their skeletal abnormalities with those observed in patients with pseudohypoparathyroidism type 1a.
New England Journal of Medicine 06/2011; 364(23):2218-26. · 53.30 Impact Factor
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Stéphanie Maupetit-Méhouas,
Virginie Mariot,
Christelle Reynès,
Guylène Bertrand,
Francois Feillet,
Jean-Claude Carel,
Dominique Simon,
Hélène Bihan,
Vincent Gajdos,
Eve Devouge,
Savitha Shenoy,
Placide Agbo-Kpati,
Anne Ronan,
Catherine Naud-Saudreau,
Anne Lienhardt, Caroline Silve,
Agnès Linglart
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ABSTRACT: Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR.
To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib.
In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA.
A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR.
Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.
Journal of Medical Genetics 10/2010; 48(1):55-63. · 6.36 Impact Factor
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Zoubida Karim,
Bénédicte Gérard,
Naziha Bakouh,
Rohia Alili,
Christine Leroy,
Laurent Beck, Caroline Silve,
Gabrielle Planelles,
Pablo Urena-Torres,
Bernard Grandchamp,
Gérard Friedlander,
Dominique Prié
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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.
New England Journal of Medicine 10/2008; 359(11):1128-35. · 53.30 Impact Factor
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ABSTRACT: PTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in five out 31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.
Human Molecular Genetics 07/2008; 17(18):2766-75. · 7.64 Impact Factor
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ABSTRACT: Hypoparathyroidism (HP) is characterized by low PTH levels, hypocalcemia, and hyperphosphatemia. Heterozygous mutations in pre-pro-PTH or the calcium-sensing receptor (CaSR) cause some forms of autosomal dominant HP (AD-HP). Furthermore, homozygous mutations in glial cells missing B (GCMB) have been implicated in autosomal recessive HP (AR-HP). In most other HP patients, however, the molecular defect remains undefined.
Our objectives were to determine the genetic defect in the affected members of two unrelated families with AD-HP and define the underlying disease mechanism.
Several family members affected by AD-HP were investigated. The proband in family A had low calcium detected on routine blood testing, whereas the proband in family B had symptomatic hypocalcemia.
Mutational analysis of the genes encoding pre-pro-PTH, CaSR, and GCMB was performed using PCR-amplified genomic DNA of the probands and other available members of each family. The identified GCMB mutants were characterized by Western blot analysis and luciferase reporter assay using DF-1 fibroblasts.
Two novel heterozygous mutations located in the last GCMB exon (c.1389delT and c.1399delC in families A and B, respectively) were identified that both lead to frame-shifts and replacement of the putative second transactivation domain within carboxyl-terminal region by unrelated amino acid sequence. The mutant GCMB proteins were well expressed, and both showed dose-dependent inhibition of the transactivation capacity of wild-type protein in luciferase reporter assays.
The dominant-negative effect observed in vitro for both GCMB mutations provides a plausible explanation for the impaired PTH secretion observed in the two unrelated families with AD-HP.
Journal of Clinical Endocrinology & Metabolism 07/2008; 93(9):3568-76. · 6.50 Impact Factor
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Catherine Benoist-Lasselin,
Emmanuel de Margerie,
Linda Gibbs,
Sarah Cormier, Caroline Silve,
Gisèle Nicolas,
Martine LeMerrer,
Jean-Francois Mallet,
Arnold Munnich,
Jacky Bonaventure,
Louise Zylberberg,
Laurence Legeai-Mallet
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ABSTRACT: Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies. The expression patterns of IHH (Indian hedgehog) and FGFR3 (Fibroblast Growth Factor Receptor 3) were similar with transcripts expressed throughout osteochondromas. Expression of PTHR1 (Parathyroid Hormone Receptor 1) transcripts was restricted to a narrow zone of prehypertrophic chondrocytes. Numerous cells forming osteochondromas although resembling prehypertrophic chondrocytes, stained positively with an anti-proliferating cell nuclear antigen (PCNA) antibody. In addition, ectopic expression of collagen type I and abnormal presence of osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP) were observed in the cartilaginous osteochondromas. These data indicate that most chondrocytes involved in the growth of osteochondromas can proliferate, and that some of them exhibit bone-forming cell characteristics. We conclude that in MHE, defective heparan sulfate biosynthesis caused by EXT mutations maintains the proliferative capacity of chondrocytes and promotes phenotypic modification to bone-forming cells.
Bone 08/2006; 39(1):17-26. · 4.02 Impact Factor
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ABSTRACT: Enchondromas are common intraosseous, usually benign cartilaginous tumors, that develop in close proximity to growth plate cartilage. When multiple enchondromas are present, the condition is called enchondromatosis also known as Ollier disease (WHO terminology). The estimated prevalence of Ollier disease is 1/100,000. Clinical manifestations often appear in the first decade of life. Ollier disease is characterized by an asymmetric distribution of cartilage lesions and these can be extremely variable (in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, requirement for surgery). Clinical problems caused by enchondromas include skeletal deformities, limb-length discrepancy, and the potential risk for malignant change to chondrosarcoma. The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome. Until now both Ollier disease and Maffucci syndrome have only occurred in isolated patients and not familial. It remains uncertain whether the disorder is caused by a single gene defect or by combinations of (germ-line and/or somatic) mutations. The diagnosis is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. There is no medical treatment for enchondromatosis. Surgery is indicated in case of complications (pathological fractures, growth defect, malignant transformation). The prognosis for Ollier disease is difficult to assess. As is generally the case, forms with an early onset appear more severe. Enchondromas in Ollier disease present a risk of malignant transformation of enchondromas into chondrosarcomas.
Orphanet Journal of Rare Diseases 02/2006; 1:37. · 5.83 Impact Factor
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ABSTRACT: The Ca(2+)-sensing receptor (CaSR) belongs to the class III G-protein-coupled receptors (GPCRs), which include receptors for pheromones, amino acids, sweeteners, and the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). These receptors are characterized by a long extracellular amino-terminal domain called a Venus flytrap module (VFTM) containing the ligand binding pocket. To elucidate the molecular determinants implicated in Ca(2+) recognition by the CaSR VFTM, we developed a homology model of the human CaSR VFTM from the x-ray structure of the metabotropic glutamate receptor type 1 (mGluR1), and a phylogenetic analysis of 14 class III GPCR VFTMs. We identified critical amino acids delineating a Ca(2+) binding pocket predicted to be adjacent to, but distinct from, a cavity reminiscent of the binding site described for amino acids in mGluRs, GABA-B receptor, and GPRC6a. Most interestingly, these Ca(2+)-contacting residues are well conserved within class III GPCR VFTMs. Our model was validated by mutational and functional analysis, including the characterization of activating and inactivating mutations affecting a single amino acid, Glu-297, located within the proposed Ca(2+) binding pocket of the CaSR and associated with autosomal dominant hypocalcemia and familial hypocalciuric hypercalcemia, respectively, genetic diseases characterized by perturbations in Ca(2+) homeostasis. Altogether, these data define a Ca(2+) binding pocket within the CaSR VFTM that may be conserved in several other class III GPCRs, thereby providing a molecular basis for extracellular Ca(2+) sensing by these receptors.
Journal of Biological Chemistry 12/2005; 280(45):37917-23. · 4.77 Impact Factor
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ABSTRACT: Skeletal development is a highly sophisticated process involving, as a first step, migration and condensation of mesenchymal cells into osteoprogenitor cells. These cells further differentiate into chondrocytes and osteoblasts through multiple differentiation stages requiring a set of specific transcriptional factors. Defective endochondral ossification in human is associated with a large number of inherited skeletal dysplasias caused by mutations in genes encoding extracellular matrix components, growth factors and their receptors, signaling molecules and transcription factors. This review summarizes some of the recent findings on a series of chondrodysplasias caused by mutations in FGFR3 and PTHR1, two receptors expressed in the cartilage growth plate and mediating two main signaling pathways. Data from human diseases and relevant animal models provide new clues for understanding how signaling molecules and their interaction with key transcription factors control and regulate the development and growth of long bones.
Medecine sciences: M/S 12/2005; 21(11):954-61. · 0.64 Impact Factor
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ABSTRACT: Fibroblast Growth Factor (FGF) 18 and 23 are two recently identified members of the FGF family, a family of structurally related polypeptides with diverse roles in physiological and pathological processes. Studies mostly performed in rodents and chicken have demonstrated that FGF18 is a pleiotropic growth factor involved in the development of various organs, while there are no data supporting a direct role of FGF23 in cell proliferation or differentiation either in physiology or pathology in any species. However, it is now established that FGF23 can be a humoral messenger and an important regulator of phosphate homeostasis and vitamin D metabolism. As a first step towards elucidating the roles of these FGF in human development, we examined FGF18 and FGF23 mRNA expression by in situ hybridization in whole human embryos at 30 days and 8 weeks of gestation (GW) and in specific fetal tissues at different ages. We report a highly restricted expression pattern for both FGF genes in human embryonic development.
Gene Expression Patterns 05/2005; 5(4):569-73. · 2.02 Impact Factor
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ABSTRACT: We discuss how recent findings obtained in disorders of phosphate metabolism in humans and in animal models have provided insights into the pathogenesis of renal stone formation and bone demineralization.
Mice that are null for the sodium-phosphate cotransporter (NPT)2a gene (NPT2a(-/-) mice) exhibit hypophosphataemia, increased urinary phosphate excretion, hypercalciuria and nephrolithiasis, but no bone demineralization. Mice null for the sodium-hydrogen exchanger regulatory factor (NHERF)1 (NHERF1(-/-) mice) also exhibit hypophosphataemia and increased renal phosphate excretion with decreased renal NPT2a expression, but they present with a severe sex-dependent bone demineralization. Heterozygous loss-of-function mutations in the NPT2a gene in humans induce hypophosphataemia, increased urinary phosphate excretion, hypercalciuria, nephrolithiasis in males (to date) and bone demineralization of variable severity in both sexes. Patients and experimental animals with increased circulating levels of fibroblast growth factor 23 present with hypophosphataemia, increased urinary phosphate excretion, inappropriate calcitriol synthesis and rickets/osteomalacia, but no nephrolithiasis except when treated. Low-phosphate diet in spontaneously hypercalciuric rats and disruption of the 1-alpha-hydroxylase gene in NPT2a mice prevent renal stone formation.
Increased urinary phosphate excretion is a risk factor for renal calcium stone formation when it is associated with hypercalciuria. As yet undefined interplay between NPT2a, NHERF1 and possibly other cotransporters or associated proteins in bone cells may account for the diversity of bone phenotypes observed in disorders of phosphate metabolism with impaired renal phosphate reabsorption. The pathogenesis of both renal stone and bone demineralization appear to be affected by species, sex and mutation type, among other factors.
Current Opinion in Nephrology and Hypertension 12/2004; 13(6):675-81. · 4.33 Impact Factor
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ABSTRACT: Our knowledge of phosphate balance under physiological and pathological situations has increased substantially during the last decade thanks to the molecular identification of three dissimilar families of sodium-phosphate cotransport systems, two of them almost exclusively expressed in epithelia whereas the third one has a ubiquitous expression. Intracellular proteins such as NHERF1 (sodium-proton exchanger regulatory factor 1) can interact with phosphate transporters through PDZ domains thus regulating the expression of the transporters at the membrane. Moreover, newly acknowledged paracrine/endocrine peptides, such as fibroblast growth factor 23 (FGF23), also affect the activity of phosphate transporters. Renal phosphate leak, related to invalidation (in the mouse) or to mutations (in humans) of the renal phosphate transporter NPT2a, leads to hypophosphatemia on the one hand, and to nephrolithiasis or bone demineralization on the other hand. Similar features are observed during invalidation of NHERF or in case of overproduction of FGF23. These observations highlight the importance of phosphate homeostasis in common diseases such as renal stones or bone loss.
Nephron Experimental Nephrology 02/2004; 98(2):e50-4. · 1.86 Impact Factor
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ABSTRACT: This study investigates the function of the diastrophic dysplasia sulfate transporter (DTDST) in otosclerotic bone and the effect on it of sodium fluoride (NaF).
Otosclerosis is a localized bone dystrophy with increased bone turnover. DTDST is implicated in the regulation of the bone turnover.
Primary cultures of cells were obtained from the stapes and external auditory canal (EAC) of 26 patients with otosclerosis and from nine control patients. Sulfate uptake was quantified under basal conditions and with NaF. The NaF signaling pathways were investigated using forskolin and verapamil.
The relative initial rates of sulfate uptake and the apparent Vmax values were: otosclerotic stapes > EAC > control stapes = control EAC. The sulfate uptake by the otosclerotic stapes was correlated with the loss of sensorineural hearing. The amounts of DTDST mRNA (RNase protection assay) in the four subgroups did not differ. NaF (10(-6)M, 1 hr) inhibited sulfate uptake by the otosclerotic stapes and EAC cells but not by control samples.
The authors believe that whether the increased DTDST activity is a cause or an effect of otosclerosis, it appears to be a specific target for NaF treatment.
Ontology & Neurotology 11/2003; 24(6):854-62. · 1.90 Impact Factor
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ABSTRACT: Hypothesis: This study investigates the function of the diastrophic dysplasia sulfate transporter (DTDST) in otosclerotic bone and the effect on it of sodium fluoride (NaF).
Background: Otosclerosis is a localized bone dystrophy with increased bone turnover. DTDST is implicated in the regulation of the bone turnover.
Materials and Methods: Primary cultures of cells were obtained from the stapes and external auditory canal (EAC) of 26 patients with otosclerosis and from nine control patients. Sulfate uptake was quantified under basal conditions and with NaF. The NaF signaling pathways were investigated using forskolin and verapamil.
Results: The relative initial rates of sulfate uptake and the apparent Vmax values were: otosclerotic stapes > EAC > control stapes = control EAC. The sulfate uptake by the otosclerotic stapes was correlated with the loss of sensorineural hearing. The amounts of DTDST mRNA (RNase protection assay) in the four subgroups did not differ. NaF (10-6M, 1 hr) inhibited sulfate uptake by the otosclerotic stapes and EAC cells but not by control samples.
Conclusion: The authors believe that whether the increased DTDST activity is a cause or an effect of otosclerosis, it appears to be a specific target for NaF treatment.
Otosclerosis is a bone dystrophy that involves the middle ear and bony labyrinth (1). It is one of the most frequent causes of deafness in adults, affecting perhaps 0.2 to 0.3 percent of the population in Western Europe and North America (2). Studies of autopsy material suggest that subclinical forms of this disease affect the temporal bones of 10 to 15 percent of the general population (3). Half of the cases seem to be hereditary, with autosomal-dominant transmission (4). Genetic linkage studies have shown an association between otosclerosis and markers of collagen 1A1 polymorphism (5) and the otosclerosis 1 locus on chromosome 15q25-q26.
The disease mainly affects the anterior part of the oval window (fissula ante fenestram) and the stapediovestibular joint, in which the otosclerotic lesions block movements of the stapes and disturb the sound transmission, causing conductive hearing loss. Lesions may extend to the stapes and the cochlear endosteum, giving rise to lesions of the cochlear hair cells and thus to sensorineural hearing loss (2). These cochlear lesions may be caused by the production of hydrolytic enzymes by osteoclasts and their diffusion in the inner ear fluids (6). Studies on the temporal bones of patients with otosclerosis indicate that the external auditory canal (EAC) bone is not involved in otosclerotic foci (3,7).
Microscopic examination of otosclerotic bone has shown that there is a high bone turnover, with inactive fibrous regions and active resorption foci containing numerous osteoclasts, osteoblasts, and blood vessels forming a mosaic (8).
The otosclerosis 1 locus contains a gene that encodes the sulfated connective tissue matrix protein, aggrecan (9). The sulfatation of the bone matrix glycosaminoglycans (GAG) is probably implicated in the regulation of the bone turnover by modulating the cellular response to growth factors such as fibroblast growth factor-2 (10,11). Otosclerotic stapes in cell culture show an abnormal high sulfatation of bone matrix GAG (12-14), in agreement with assays of otosclerosis bones (15). These studies suggest that the sulfated GAG is implicated in the pathogenesis of otosclerosis.
The diastrophic dysplasia sulfate transporter (DTDST) is involved in the synthesis of the sulfated GAG; it helps transport sulfate ions within connective tissue cells such as fibroblasts, chondroblasts, and osteoblasts (16). Several mutations of DTDST have been described, causing loss of transporter activity, low bone-sulfated GAG, and osteochondrodystrophies, whose clinical severity depends on the type of mutation (17). Thus, an increased DTDST activity may account for the relative high GAG sulfatation that occurs in otosclerosis.
Sodium fluoride (NaF) appears to slow the deterioration of bone conduction in otosclerosis (18), perhaps by inhibiting hydrolytic enzymes, such as trypsin, that diffuse from the diseased area into the cochlea (19). The temporal bones of patients treated with NaF contain mainly inactive otosclerotic foci (20). Although the action of NaF on bone has been extensively studied (21), the molecular mechanisms underlying this action remain poorly understood. As NaF reduces bone turnover, and DTDST is implicated in the regulation of the bone metabolism, we have investigated the effect of NaF on DTDST by examining two signaling pathways (adenylate cyclase/cAMP and intracellular Ca2+).
We find that the DTDST activity in cultures of stapes and EAC bones taken from patients with otosclerosis is increased. The DTDST activity in the otosclerotic stapes is correlated with the preoperative sensorineural hearing loss and is inhibited by NaF. NaF appears to inhibit DTDST activity by blocking the intracellular calcium signaling pathway in the stapes and the EAC. The cAMP pathway may also be involved in the inhibition of the DTDST activity by NaF in the EAC.
Ontology & Neurotology 10/2003; 24(6):854-862. · 1.90 Impact Factor
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ABSTRACT: Close temporal and spatial relationships between Pthrp and Pthr1 gene expression are reported during fetal life in rats, suggestive of a developmental role via a paracrine signaling pathway. In agreement, disruption of this signaling pathway is associated with developmental defects, as documented in mice and humans. Surprisingly, however, only few organs are affected. We report here PTHrP and PTHR1 gene expression during human embryo-fetal development. We describe three patterns: in some organs, both genes are active ('hand-in-glove' fashion), while in others either PTHrP or PTHR1 transcripts are detected. In addition, in some tissues, expression of PTHrP or PTHR1 genes is transient. Abnormal development has been documented only for organs expressing both genes. The patterns that we observe are compatible with specific roles for each gene not mediated through the PTHrP/PTHR1 signaling pathway.
Gene Expression Patterns 04/2003; 3(1):59-63. · 2.02 Impact Factor
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ABSTRACT: The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans, FGFR3 signaling does not down-regulate the main players of the IHH/PTHR1 pathway. Furthermore, we show that cells within the bone-perichondrial ring in controls and patients express IHH, PTHR1, and type 10 and type 1 collagen transcripts, suggesting that bone-perichondrial ring formation involves cells of both chondrocytic and osteoblastic phenotypes.
American Journal Of Pathology 11/2002; 161(4):1325-35. · 4.89 Impact Factor
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Dominique Prié,
Virginie Huart,
Naziha Bakouh,
Gabrielle Planelles,
Olivier Dellis,
Bénédicte Gérard,
Philippe Hulin,
François Benqué-Blanchet, Caroline Silve,
Bernard Grandchamp,
Gérard Friedlander
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ABSTRACT: Epidemiologic studies suggest that genetic factors confer a predisposition to the formation of renal calcium stones or bone demineralization. Low serum phosphate concentrations due to a decrease in renal phosphate reabsorption have been reported in some patients with these conditions, suggesting that genetic factors leading to a decrease in renal phosphate reabsorption may contribute to them. We hypothesized that mutations in the gene coding for the main renal sodium-phosphate cotransporter (NPT2a) may be present in patients with these disorders.
We studied 20 patients with urolithiasis or bone demineralization and persistent idiopathic hypophosphatemia associated with a decrease in maximal renal phosphate reabsorption. The coding region of the gene for NPT2a was sequenced in all patients. The functional consequences of the mutations identified were analyzed by expressing the mutated RNA in Xenopus laevis oocytes.
Two patients, one with recurrent urolithiasis and one with bone demineralization, were heterozygous for two distinct mutations. One mutation resulted in the substitution of phenylalanine for alanine at position 48, and the other in a substitution of methionine for valine at position 147. Phosphate-induced current and sodium-dependent phosphate uptake were impaired in oocytes expressing the mutant NPT2a. Coinjection of oocytes with wild-type and mutant RNA indicated that the mutant protein had altered function.
Heterozygous mutations in the NPT2a gene may be responsible for hypophosphatemia and urinary phosphate loss in persons with urolithiasis or bone demineralization.
New England Journal of Medicine 10/2002; 347(13):983-91. · 53.30 Impact Factor
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Nephrology Dialysis Transplantation 07/2002; 17(6):958-61. · 3.40 Impact Factor
