Thanatophoric Dysplasia Molecular Basis of the Disease

Thanatophoric dysplasia is a lethal form of neonatal dwarfism, with two clinical types. Type 1 is characterized by micromelia with femoral bowing and, uncommonly, a cloverleaf skull. Type 2 is characterized by micromelia without femoral bowing and with uniform presence of moderate to severe cloverleaf skull. Thanatophoric dyspla-sia type 1 is caused by mutations in FGFR3 (R248C, S249C, G370C, S371C, and Y373C) that introduce an unpaired cysteine residue into the protein. Inappropriate pairing of these cysteines is hypothesized to cause activation of the receptor in the absence of its ligand (constitutive receptor activation). The K650E mutation in FGFR3 causes thanatophoric dysplasia type 2 by a different mechanism. This mutation involves a charge reversal, whereas K650N, which does not have the same charge reversal, causes hypochondroplasia. The X807 read-through mutations are quite rare, but interesting because the natural stop codon is destroyed, resulting in additional amino acids at the car-boxyl end of the protein (Hemoglobin Constant Spring is another example). Even more interesting, given the proposed dominant gain-of-function nature of FGFR3 mutations in thanatophoric dysplasia type 1, is the fact that the presence of 141 additional amino acids at the carboxyl end of the protein should enhance the receptor function.

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