title: Thanatophoric dysplasia caused by double missense FGFR3 mutations.
abstract: Thanatophoric dysplasia is a lethal chondrodysplasia caused by heterozygous fibroblast growth factor receptor 3 (FGFR3) missense mutations. Mutations have been identified in several domains of the receptor. The most frequent mutations (p.R248C, p.S249C, p.Y373C) create a cysteine residue within the extracellular domain, whereas the others eliminate the termination codon (p.X807R, p.X807C, p.X807G, p.X807S, p.X807W). Here, we report a unique patient with thanatophoric dysplasia and a double de novo FGFR3 mutation, located on the same allele, (c.[1620C>A;1454A>G]), which corresponds to p.[N540K;Q485R]. The p.N540K mutation is associated with 60% of patients with hypochondroplasia and the p.Q485R mutation is a novel mutation located in a highly conserved domain of FGFRs. Evidence for the structural impact of the two concurrent missense mutations was achieved using protein alignments and three-dimensional structural prediction, in agreement with our modeling of the FGFR3 structure. In this patient with thanatophoric dysplasia, we conclude that the presence of the double FGFR3 missense mutation on the same allele alters the receptor structure, holding the receptor in its fully activated state, thus leading to lethal chondrodysplasia.
authors.affiliation: INSERM U781, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pannier
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Solange
authors.initials: S
authors.lastname: Heuertz
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurent
authors.initials: L
authors.lastname: Schibler
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D037881:Aborted Fetus; D000028:Abortion, Induced; D000483:Alleles; D000595:Amino Acid Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013796:Thanatophoric Dysplasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology
chemical_list: D051498:Receptor, Fibroblast Growth Factor, Type 3