Severe complications in a child with achondroplasia and two FGFR3 mutations on the same allele

ArticleinAmerican Journal of Medical Genetics Part A 140(3):284-90 · February 2006with9 Reads
DOI: 10.1002/ajmg.a.31084 · Source: PubMed
We describe a unique case of achondroplasia with associated complications, including severe respiratory problems. Molecular analysis of the fibroblast growth factor receptor type 3 (FGFR3) gene in this patient showed the common p.G380R mutation and a second novel p.L377R mutation. An allele-specific PCR demonstrated that these mutations were on the same allele (cis). Both mutations were not present in the parents and appear to have occurred de novo. To our knowledge, this is the first report in the literature on an achondroplasia patient with two FGFR3 mutations on the same allele.
    • "Bowing of the femora is not a universal characteristic of achondroplasia, although it is sometimes observed clinically (e.g. Boulet et al., 2009; Cheema et al., 2003; Rump et al., 2006). The bowing of the femora may be a reaction to the more commonly observed tibial bowing. "
    [Show abstract] [Hide abstract] ABSTRACT: An opportunity to explore osteological features of a form of disproportionate dwarfism is presented by a recent archaeological discovery. Excavation of a predominately nineteenth century Dutch cemetery from the rural, agricultural village of Middenbeemster revealed an older adult female with skeletal changes consistent with achondroplasia. The most marked features are a rhizomelic pattern of shortened and thickened upper and lower limbs, frontal bossing and a moderately depressed nasal bridge, small lumbar neural canals with short pedicles, bowing of the femora and tibiae, and short stature (130.0 ± 5 cm). However, some common features of achondroplasia like cranial base reduction and shortened fingers and toes are absent. The alternative diagnosis of a more mild form of short-limbed dwarfism, hypochondroplasia, is explored and aided by archival identification of the individual and her offspring. Five offspring, including three perinates, a 10-year-old daughter, and a 21-year-old son, are analysed for evidence of an inherited skeletal dysplasia. The unique addition of family history to the paleopathological diagnostic process supports a differential outcome of hypochondroplasia. This combination of osteological and archival data creates a unique opportunity to track the inheritance and manifestation of a rare disease in a past population.
    Full-text · Article · Dec 2013
    • "The G346E mutation in FGFR3 has been reported to cause achondroplasia [30], and is often cited in the literature as a genetic cause for the disorder [12,242526272829. However, there are no biochemical studies of the effect of this mutation on FGFR3 phosphorylation in the literature. "
    [Show abstract] [Hide abstract] ABSTRACT: Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism.
    Full-text · Article · Apr 2012
    • "D10S1483 (10q26), and D19S566 (19p13.1). As discussed above, they were chosen for their high heterozygosity, and for their previous linkage to Class III malocclusion (Yamaguchi et al., 2005) or proximity to candidate regions to skeletal disorders (Stein et al., 2004; Yoshida et al., 2004; Yamaguchi et al., 2005; Freitas et al., 2006; Jacob et al., 2006; Kress et al., 2006; Rump et al., 2006; Stevens and Roeder, 2006 ). D1S234 is located relatively close to RUNX3, D6S1689 to RUNX2, D4S3038 to FGFR3, D7S503 to TWIST, and D10S1483 to FGFR2. "
    [Show abstract] [Hide abstract] ABSTRACT: The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies.
    Full-text · Article · Aug 2011
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