By using a combination of single-strand conformation polymorphism (SSCP) and direct sequencing of amplified exons, Rousseau et al. (1995) found 3 different heterozygous base substitutions in the chain termination codon of FGFR3 in 5 of 15 TD type I patients (187600) without cloverleaf skull (codon 807, nucleotides 2458 and 2460). These mutations were expected to give rise to a protein elongated by 141 amino acids, as the mRNA continues to be translated through a 423-bp region until another in-frame stop codon is reached. This would result in a highly hydrophobic domain with an alpha-helix structure at the C-terminal end of the full-length protein. This was the first report of a stop codon mutation in an FGFR gene. Absence of stop codon mutations in the healthy parents and the finding of advanced paternal age at the time of conception gave support to the view that de novo mutations of paternal origin were involved. Of the 5 patients, 2 had a T-to-G transversion in the TGA stop codon, 2 had a T-to-A transversion in the TGA stop codon, and 1 had an A-to-T transversion in the TGA stop codon. The first of these mutations, TGA to GGA, represents ter807 to gly; the second, TGA to AGA, represents a ter807-to-arg change (134934.0008); and the third, TGA to TGT, represents a ter807-to-cys change (134934.0009). The classic example of a stop codon mutation is that found in the alpha-globin chain variant hemoglobin Constant Spring (141850.0001).
