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      Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3.

      Nature genetics
      Achondroplasia, genetics, metabolism, pathology, Animals, Bone Diseases, Developmental, DNA, Deafness, Ear, Inner, abnormalities, growth & development, Female, Gene Targeting, Homozygote, Humans, Male, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Osteogenesis, physiology, Phenotype, Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 3, Receptors, Fibroblast Growth Factor

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          Abstract

          Fibroblast growth factor receptor 3 (Fgfr3) is a tyrosine kinase receptor expressed in developing bone, cochlea, brain and spinal cord. Achondroplasia, the most common genetic form of dwarfism, is caused by mutations in FGFR3. Here we show that mice homozygous for a targeted disruption of Fgfr3 exhibit skeletal and inner ear defects. Skeletal defects include kyphosis, scoliosis, crooked tails and curvature and overgrowth of long bones and vertebrae. Contrasts between the skeletal phenotype and achondroplasia suggest that activation of FGFR3 causes achondroplasia. Inner ear defects include failure of pillar cell differentiation and tunnel of Corti formation and result in profound deafness. Our results demonstrate that Fgfr3 is essential for normal endochondral ossification and inner ear development.

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          Embedding in epoxy resins for ultrathin sectioning in electron microscopy.

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            Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.

            The c-abl proto-oncogene, which encodes a cytoplasmic protein-tyrosine kinase, is expressed throughout murine gestation and ubiquitously in adult mouse tissues. However, its levels are highest in thymus, spleen, and testes. To examine the in vivo role of c-abl, the gene was disrupted in embryonic stem cells, and the resulting genetically modified cells were used to establish a mouse strain carrying the mutation. Most mice homozygous for the c-abl mutation became runted and died 1 to 2 weeks after birth. In addition, many showed thymic and splenic atrophy and a T and B cell lymphopenia.
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              Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.

              Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. Mutations causing achondroplasia are in FGFR3, suggesting that mutations in this gene may cause TD. A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder.
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