We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.
We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.
We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.
Thus, it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
Achondroplasia (ACH), the most common cause of chondrodysplasia in man (1 in 15,000 live births), is an autosomal dominant condition of unknown origin characterized by short-limbed dwarfism and macrocephaly.
These results together with our earlier observation that achondroplasia results from constitutive activation of the related receptor FGFR3, leads to the prediction that other malformation syndromes attributed to FGFRs, such as Pfeiffer syndrome and Thanatophoric dysplasia, also arise from constitutive receptor activation.
Given the homogeneity of mutations within the fibroblast growth factor receptor 3 (FGFR3) gene in the vast majority of patients with Ach, FGFR3 mutational analysis can be offered in every instance where a short-limb disorder is ultrasonographically detected in the latter stages of pregnancy.
Funipuncture was performed and DNA analysis of fetal blood demonstrated the presence of the GR380R fibroblast growth factor receptor 3 (FGFR3), which is specifically associated with achondroplasia.
Mutations in the type II collagen gene account for most spondyloepiphyseal dysplasia and spondyloepiphyseal dysplasia-like clinical disorders, whereas mutations in the fibroblast growth factor receptor 3 gene are responsible for achondroplasia, thanatophoric dysplasia, and hypochondroplasia.
0.1 microM endothelin 3 (ET3), 1 microM angiotensin II (AII), and 10 microM acetylcholine (Ach) significantly increased AVP release; ET3 (C 1.78 +/- 0.20 vs. ET3 6.85 +/- 1.86 pg/2 x 10(6) cells, N = 8, P < 0.02); AII (C 1.29 +/- 0.38 vs. AII 27.80 +/- 7.09 pg/2 x 10(6) cells, N = 5, P < 0.05) and Ach (C 1.14 +/- 0.33 vs. Ach 2.68 +/- 0.58 pg/2 x x10(6) cells, N = 6, P < 0.05).
0.1 microM endothelin 3 (ET3), 1 microM angiotensin II (AII), and 10 microM acetylcholine (Ach) significantly increased AVP release; ET3 (C 1.78 +/- 0.20 vs. ET3 6.85 +/- 1.86 pg/2 x 10(6) cells, N = 8, P < 0.02); AII (C 1.29 +/- 0.38 vs. AII 27.80 +/- 7.09 pg/2 x 10(6) cells, N = 5, P < 0.05) and Ach (C 1.14 +/- 0.33 vs. Ach 2.68 +/- 0.58 pg/2 x x10(6) cells, N = 6, P < 0.05).
0.1 microM endothelin 3 (ET3), 1 microM angiotensin II (AII), and 10 microM acetylcholine (Ach) significantly increased AVP release; ET3 (C 1.78 +/- 0.20 vs. ET3 6.85 +/- 1.86 pg/2 x 10(6) cells, N = 8, P < 0.02); AII (C 1.29 +/- 0.38 vs. AII 27.80 +/- 7.09 pg/2 x 10(6) cells, N = 5, P < 0.05) and Ach (C 1.14 +/- 0.33 vs. Ach 2.68 +/- 0.58 pg/2 x x10(6) cells, N = 6, P < 0.05).
The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity: 100% of patients examined exhibited mutations in the transmembrane domain of FGFR-3.
The heterozygous phenotype has been likened to achondroplastic dwarfism in humans (ACH), which has recently been shown to be the result of mutations in the transmembrane region of the fibroblast growth factor receptor 3 (FGFR3) gene.
Using our established techniques for single-cell ratiometric real-time calcium image analysis, we defined the nature of the basic fibroblast growth factor (bFGF)-induced calcium signal in human diploid fibroblasts, and, in blinded studies, have analyzed the bFGF-induced signals from 18 independent fibroblast cell lines, including multiple lines from patients with known mutant alleles of FGFR3 and syndromes of Ach or TD.
Using our established techniques for single-cell ratiometric real-time calcium image analysis, we defined the nature of the basic fibroblast growth factor (bFGF)-induced calcium signal in human diploid fibroblasts, and, in blinded studies, have analyzed the bFGF-induced signals from 18 independent fibroblast cell lines, including multiple lines from patients with known mutant alleles of FGFR3 and syndromes of Ach or TD.
The cells with the chimera bearing the ACH mutation were more rapidly responsive to ligand with less sustained MAPK activation, indicative of a preactivated or primed condition and consistent with the view that these mutations weaken ligand control of FGFR3 function.
Mutations of COL2A1, COL9A2, COL10, and FGFR3 have been reported previously in the Strudwick type of SEMD, multiple epiphyseal dysplasia type 2 (EDM2), the Schmid type of metaphyseal dysplasia, and in achondroplasia, respectively, and the pseudoachondroplasia (PSACH) locus has been mapped to chromosome 19p12.
Heterozygous mutations of the gene encoding the fibroblast growth factor receptor 3 (FGFR3) have been found in persons with achondroplasia, thanatophoric dysplasia, and hypochondroplasia.