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In classical achondroplasia (Ach), a glycine residue is replaced by an arginine at codon 380 in exon 10 of the fibroblast growth factor receptor 3 gene (FGFR3). Here we report on a mother and daughter with hypochondroplasia (Hch) caused by a new heterozygous double mutation (1138_1139GG > AA) at the same codon 380, but encoding a lysine instead of the usual arginine. Previous functional assays of these codon 380 amino acid substitutions demonstrated a lesser activation of receptor signaling by lysine compared to arginine [Webster and Donoghue, 1996; EMBO J 15:520-527]. This could explain the milder phenotype observed in our patients. Several other rare double mutations were previously described in both FGFR2 and FGFR3 and interpreted as resulting from positive selection of spermatogonial cells owing to gain-of-function in the encoded protein [Goriely et al., 2005; Proc Natl Acad Sci USA 102:6051-6056]. The present case contributes additional support for this hypothesis.

Original publication

DOI

10.1002/ajmg.a.31556

Type

Journal article

Journal

Am J Med Genet A

Publication Date

15/02/2007

Volume

143

Pages

355 - 359

Keywords

Achondroplasia, Adult, Aged, Amino Acid Substitution, Base Sequence, Codon, Female, Glycine, Humans, Lysine, Molecular Sequence Data, Mutation, Phenotype, Radiography, Receptor, Fibroblast Growth Factor, Type 3, Sequence Analysis, DNA, Skull