The Experts below are selected from a list of 363 Experts worldwide ranked by ideXlab platform
Harald Juppner - One of the best experts on this subject based on the ideXlab platform.
-
hypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with jansen s metaphyseal chondrodysplasia
The Journal of Clinical Endocrinology and Metabolism, 2009Co-Authors: Whitney W Brown, Harald Juppner, Craig B Langman, Heather E Price, Emily G Farrow, Kenneth E White, Kenneth L MccormickAbstract:Context: Previous studies have suggested a regulatory relationship between serum phosphorus, vitamin D, and fibroblast growth factor 23 (FGF23), a hormone that promotes renal excretion of phosphate. Despite these associations, the identity of the primary regulator of serum FGF23 is unresolved. Jansen’s metaphyseal chondrodysplasia is a rare autosomal dominant disorder associated with Short-Limbed Dwarfism and other characteristic skeletal abnormalities. This condition is caused by mutations in the PTH/PTHrP receptor that result in ligand-independent cAMP accumulation, thus rendering the receptor constitutively active. These patients typically exhibit asymptomatic hypercalcemia and hypophosphatemia despite low or undetectable serum levels of PTH and PTHrP. Evidence Acquisition: A literature search revealed that serum FGF23 levels had not been studied in patients with Jansen’s syndrome, a disorder in which the biochemical features present a unique opportunity to study the possible relationship between FGF23...
-
a form of jansen s metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone pth pth related peptide receptor mutation
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Murat Bastepe, Harald Juppner, Annick Raasrothschild, Justin Silver, Irit Weissman, S Wientroub, David GillisAbstract:A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen’s metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to Short-Limbed Dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findin...
-
constitutively activated receptors for parathyroid hormone and parathyroid hormone related peptide in jansen s metaphyseal chondrodysplasia
The New England Journal of Medicine, 1996Co-Authors: Ernestina Schipani, Harald Juppner, Craig B Langman, A M Parfitt, G S Jensen, S Kikuchi, Sang Whay Kooh, William G ColeAbstract:Background An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone–related peptide (PTHrP) was recently found in a patient with Jansen's metaphyseal chondrodysplasia, a rare form of Short-Limbed Dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansen's disease. Methods Exons encoding the PTH–PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products. Results The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives o...
-
a constitutively active mutant pth pthrp receptor in jansen type metaphyseal chondrodysplasia
Science, 1995Co-Authors: Ernestina Schipani, Klaus Kruse, Harald JuppnerAbstract:A single heterozygous nucleotide exchange in exon M2 of the gene encoding the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor was identified in a patient with Jansen-type metaphyseal chondrodysplasia, which changes a strictly conserved histidine residue at position 223 in the receptor9s first intracellular loop to arginine. Constitutive, ligand-independent adenosine 39,59-monophosphate accumulation was observed in COS-7 cells expressing the mutant PTH-PTHrP receptor but not in cells expressing the wild-type receptor. This finding explains the severe ligand-independent hypercalcemia and hypophosphatemia, and most likely the abnormal formation of endochondral bone, in this rare form of Short-Limbed Dwarfism.
Philippe Moerman - One of the best experts on this subject based on the ideXlab platform.
-
a new lethal chondrodysplasia with spondylocostal dysostosis multiple internal anomalies and dandy walker cyst
Clinical Genetics, 2008Co-Authors: Philippe Moerman, Kamiel Vandenberghe, J P Fryns, M Haspeslagh, J M LauwerynsAbstract:We describe here a female infant, exhibiting lethal Short-Limbed Dwarfism. The condition superficially resembled achondrogenesis. However, unlike achondrogenesis there was an associated severe spondylocostal dysostosis and major non-skeletal anomalies, particularly a cerebellar Dandy-Walker cyst, cardiovascular and urogenital malformations. The chondro-osseous morphology was nonspecific. The case is believed to be unique. It is therefore suggested that this constellation of anomalies constitutes a “new” lethal syndrome, different from the delineated chondrodysplasias.
-
Short Limbed Dwarfism, genital hypoplasia, sparse hair, and vertebral anomalies: a variant of Ellis-van Creveld syndrome?
Journal of medical genetics, 1993Co-Authors: Jean-pierre Fryns, Philippe MoermanAbstract:A male newborn with acromesomelic Short Limbed Dwarfism, genital hypoplasia, and vertebral anomalies is reported. As the child had an important number of clinical and radiological symptoms seen in patients with Ellis-van Creveld syndrome, we raise the question of whether he may represent a variant example of this syndrome despite the absence of cardinal symptoms such as postaxial polydactyly and ectodermal changes (nail hypoplasia).
Avner Yayon - One of the best experts on this subject based on the ideXlab platform.
-
fibroblast growth factor receptor 3 as a therapeutic target for achondroplasia genetic Short Limbed Dwarfism
Current Drug Targets, 2003Co-Authors: David Aviezer, Myriam Golembo, Avner YayonAbstract:Achondroplasia, the most common form of human Dwarfism is a sporadic autosomal dominant condition that occurs in approximately 1:20,000 births. The major clinical outcome of Achondroplasia is attenuated growth, rhizomelic Shortening of the long bones and craniofacial abnormalities. As of today there is no pharmacological treatment for Achondroplasia. Some improvement in the patients well being and daily function can be achieved by a surgical limb lengthening procedure. Growth hormone treatment seems to have only modest Short term success and to lack long term benefits. Achondroplasia results from a single point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, there is a Glycine to Arginine substitution at position 380 within the FGFR-3 transmembrane domain leading to receptor overactivation. This FGF receptor tyrosine kinase is expressed by chondrocytes in the growth plate of developing long bones and plays a crucial role in bone growth. Genetic disruption of the FGFR-3 gene in mice leads to a remarkable increase in the length of the vertebral column and long bones. This suggests that overaction of FGFR3 signaling may specifically impair chondrocyte function within the epiphyseal growth plates and cause Achondroplasia. Reconstituted normal bone growth may therefore be achieved by attenuation of FGFR3 signaling in the appropriate cells within the growth plate. It is highly conceivable that drug development strategies aimed either towards blocking extracellular ligand binding or towards intracellular checkpoints along the FGF signal transduction cascade, may prove successful in the treatment of Achondroplasia. This review focuses on the possible approaches for developing a drug for Achondroplasia and related skeletal disorders, using chemical, biochemical and molecular strategies.
Tetsuo Kunieda - One of the best experts on this subject based on the ideXlab platform.
-
Short-Limbed Dwarfism: slw Is a New Allele of Npr2 Causing Chondrodysplasia
The Journal of heredity, 2007Co-Authors: Chizuru Sogawa, Takehito Tsuji, Yusuke Shinkai, Kentaro Katayama, Tetsuo KuniedaAbstract:Short-Limbed Dwarfism (SLW) is a new mutant mouse characterized by a dwarf phenotype with markedly Short body, limbs, and tail. In the present study, we investigated the skeletal phenotypes of the SLW mouse and determined the chromosomal localization to identify the gene responsible for the phenotypes (slw). Skeletal preparations stained with alcian blue and alizarin red revealed that longitudinal growth of the extremities of the affected (slw/slw) mice was significantly reduced in comparison with that of normal mice, whereas the positions and numbers of skeletal elements were normal. Histological examination of tibial growth plates of the affected mice showed that the numbers of proliferating and hypertrophic chondrocytes were obviously diminished. These phenotypes resembled to those of human chondrodysplasias caused by defective chondrocyte proliferation and differentiation. We mapped the slw locus on an 11.7-cM interval of the proximal region of mouse chromosome 4 by linkage analysis. Furthermore, allelism test using Npr2 cn locus, a mutant allele of Npr2 gene encoding a natriuretic peptide receptor B, revealed that slw locus is an allele of the Npr2 gene. These results suggest that the dwarf phenotype of the SLW mouse is caused by the disturbed endochondral ossification, and a mutation in the Npr2 gene is expected to be responsible for the phenotypes of the SLW mouse.
-
Short-Limbed Dwarfism: slw Is a New Allele of Npr2 Causing Chondrodysplasia
2007Co-Authors: Chizuru Sogawa, Takehito Tsuji, Yusuke Shinkai, Kentaro Katayama, Tetsuo KuniedaAbstract:Short-Limbed Dwarfism (SLW) is a new mutant mouse characterized by a dwarf phenotype with markedly Short body, limbs, and tail. In the present study, we investigated the skeletal phenotypes of the SLW mouse and determined the chromosomal localization to identify the gene responsible for the phenotypes (slw). Skeletal preparations stained with alcian blue and alizarin red revealed that longitudinal growth of the extremities of the affected (slw/slw) mice was significantly reduced in comparison with that of normal mice, whereas the positions and numbers of skeletal elements were normal. Histological examination of tibial growth plates of the affected mice showed that the numbers of proliferating and hypertrophic chondrocytes were obviously diminished. These phenotypes resembled to those of human chondrodysplasias caused by defective chondrocyte proliferation and differentiation. We mapped the slw locus on an 11.7-cM interval of the proximal region of mouse chromosome 4 by linkage analysis. Furthermore, allelism test using Npr2cn locus, a mutant allele of Npr2 gene encoding a natriuretic peptide receptor B, revealed that slw locus is an allele of theNpr2 gene. These results suggest that the dwarf phenotype of the SLW mouse is caused by the disturbed endochondral ossification, and a mutation in the Npr2 gene is expected to be responsible for the phenotypes of the SLW mouse. The skeleton of vertebrates is formed by 2 different processes, intramembranous and endochondral ossifications. Intramem
Gregory M. Acland - One of the best experts on this subject based on the ideXlab platform.
-
COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia
Mammalian Genome, 2010Co-Authors: Orly Goldstein, Anna Kukekova, Tatyana N. Kuznetsova, Susan E. Pearce-kelling, Gustavo D. Aguirre, Richard Guyon, Jennifer Johnson, Gregory M. AclandAbstract:Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2 , respectively. Affected dogs exhibit Short-Limbed Dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5′ end of COL9A2 that cosegregates with drd2 . Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.