Achondroplasia, the most common cause of chondrodysplasia in man (1 in 15,000 
live births), is a condition of unknown origin characterized by short-limbed 
dwarfism and macrocephaly. More than 90% of cases are sporadic and there is an 
increased paternal age at the time of conception of affected individuals, 
suggesting that de novo mutations are of paternal origin. Affected individuals 
are fertile and achondroplasia is transmitted as a fully penetrant autosomal 
dominant trait, accounting for rare familial forms of the disease (10%). In 
contrast, homozygous achondroplasia is usually lethal in the neonatal period and 
affects 25% of the offspring of matings between heterozygous achondroplasia 
parents. The gene responsible for achondroplasia has been mapped to chromosome 
4p16.3 (refs 7, 8); the genetic interval encompassing the disease gene contains 
a member of the fibroblast-growth-factor receptor (FGFR3) family which is 
expressed in articular chondrocytes. Here we report the finding of recurrent 
missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 
protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic 
cases and 6 unrelated familial forms of achondroplasia. We show that the mutant 
genotype segregates with the disease in these families. Thus it appears that 
recurrent mutations of a single amino acid in the transmembrane domain of the 
FGFR3 protein account for all cases (23/23) of achondroplasia in our series.