Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia

Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia

“…Five mutations result in speci®c cysteine substitutions in FGFR3 (R248C, S249C, G370C, S371C, Y373C), six mutations eliminate the stop codon and result in 141-amino acid C-terminal extension (J807G, J807R, J807L, J807C l[2421ApT], J807C [2421ApC], J807W), and one mutation leads to a K650M substitution in FGFR3 (Rousseau et al, 1995;Tavormina et al, 1995;Bonaventure et al, 1996;Rousseau et al, 1996a;Bellus et al, 1997;Kitoh et al, 1998;Wilcox et al, 1998;Passos-Bueno et al, 1999). The majority of cases Coronal synostosis, speci®c bone anomalies of the hands and feet, but without any of classical craniosynostosis syndromes P250R (Pro250Arg) C-AN Shallow orbits, proptosis, craniosynostosis, maxillary hypoplasia, and acanthosis nigricans A391E (Ala391Glu) TD1, thanatophoric dysplasia type I (Rousseau et al, 1995;Tavormina et al, 1995;Bonaventure et al, 1996;Rousseau et al, 1996a;Bellus et al, 1997;Kitoh et al, 1998;Wilcox et al, 1998;Passos-Bueno et al, 1999); TD2, thanatophoric dysplasia type II (Tavormina et al, 1995;Wilcox et al, 1998); ACH, achondroplasia (Rousseau et al, 1994;Bellus et al, 1995a;Ikegawa et al, 1995); HCH, hypochondroplasia (Bellus et al, 1995b;Prinos et al, 1995;Rousseau et al, 1996b;Deutz-Terlouw et al, 1997;Grigelioniene  et al, 1998;Prinster et al, 1998); PLSD-SD, platyspondylic lethal skeletal dysplasia, San Diego type (Brodie et al, 1999;Passos-Bueno et al, 1999); SADDAN, severe achondroplasia with developmental delay and acanthosis nigricans (Tavormina et al, 1999); NCS, non-syndromic craniosynostosis (Bellus et al, 1996;Muenke et al, 1997); C-AN, Crouzon with acanthosis nigricans <...>…”

Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

“…Other mutations of the same residue in FGFR3 to different amino acid residues have also been associated with HCH; these mutations are N540T (27) and N540S (28). Furthermore, mutation of the N549 residue in FGFR2 to a histidine (29) or threonine (18) also occurs at the paralogous position to the mutation N546K we identified in FGFR1.…”

Prenatal diagnosis of hypochondroplasia: Report of two cases

“…Furthermore, the same fetus presented mild tibia bowing that has been described in fetuses with more severe phenotype. Although HCH individuals carrying the N540K mutation are characterized by a relatively uniform phenotype [Rousseau et al, 1996;Prinster et al, 1998;Grigelioniene et al, 2000], variable expressivity cannot be excluded as indicated by the report of one patient with the N540K mutation presenting with craniosynostosis [Angle et al, 1998], or considering reports of clinical variability of other HCH FGFR3 mutations, like N540S [Mortier et al, 2000;Thauvin-Robinet et al, 2003] and N540T [Deutz-Terlouw et al, 1998]. Almost all prenatally diagnosed HCH patients that were studied by molecular methods, including the two fetuses presented here, carried the N540K FGFR3 mutation, with a more severe phenotype compared to patients with other FGFR3 mutations or unlinked to 4p16.3 [Rousseau et al, 1996;Prinster et al, 1998;Grigelioniene et al, 2000].…”

“…Clinical heterogeneity has been associated with either different mutations in the FGFR3 gene or with cases unlinked to chromosome 4 (chromosomal locus 4p16.3). Seven pathogenic amino acid substitutions in the FGFR3 gene have been identified in HCH patients: N540K [Bellus et al, 1995;Prinos et al, 1995], N540T [Deutz-Terlouw et al, 1998], N540S [Mortier et al, 2000], I538V [Grigelioniene et al, 1998], N328I [Winterpacht et al, 2000], K650N and K650Q [Bellus et al, 2000]. The recurrent N540K mutation accounts for about 70% of all reported patients.…”