Dj. Wilkin et al., MUTATIONS IN FIBROBLAST-GROWTH-FACTOR RECEPTOR-3 IN SPORADIC CASES OFACHONDROPLASIA OCCUR EXCLUSIVELY ON THE PATERNALLY DERIVED CHROMOSOME, American journal of human genetics, 63(3), 1998, pp. 711-716
More than 97% of achondroplasia cases are caused by one of two mutatio
ns (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGF
R3) gene, which results in a specific amino acid substitution, G380R.
Sporadic cases of achondroplasia have been associated with advanced pa
ternal age, suggesting that these mutations occur preferentially durin
g spermatogenesis. We have determined the parental origin of the achon
droplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorph
isms were identified in the FGFR3 gene, within close proximity to the
achondroplasia mutation site. Ninety-nine families, each with a sporad
ic case of achondroplasia in a child, were analyzed in this study. In
this population, the achondroplasia mutation occurred on the paternal
chromosome in all 40 cases in which parental origin was unambiguous. T
his observation is consistent with the clinical observation of advance
d paternal age resulting in new cases of achondroplasia and suggests t
hat factors influencing DNA replication or repair during spermatogenes
is, but not during oogenesis, may predispose to the occurrence of the
G1138 FGFR3 mutations.