1. ¹INSERM U 393 Hôpital Necker, Paris cedex 15, France
2. ²Children's Hospital, University of Mainz, Germany
3. ³Institute of Human Genetics, Central Parkway, Newcastle upon Tyne, UK
4. ⁴Institut Curie, CNRS UMR 146, Centre Universitaire Paris Sud, Orsay, France

Correspondence: Dr J Bonaventure, Institut Curie, CNRS UMR 146, Centre Universitaire Paris-Sud, 91400 Orsay, France. Tel: +33 1 69 86 71 80; Fax: +33 1 69 86 30 51; E-mail: jacky.bonaventure@curie.u-psud.fr

Received 9 February 2006; Revised 8 May 2006; Accepted 6 June 2006; Published online 16 August 2006.

Abstract

Achondroplasia (ACH) and hypochondroplasia (HCH) are two autosomal-dominant skeletal disorders caused by recurrent missense FGFR3 mutations in the transmembrane (TM) and tyrosine kinase 1 (TK1) domains of the receptor. Although 98% of ACH cases are accounted for by a single G380R substitution in the TM, a common mutation (N540K) in the TK1 region is detected in only 60–65% of HCH cases. The aim of this study was to determine whether the frequency of mutations in patients with HCH was the result of incomplete mutation screening or genetic heterogeneity. Eighteen exons of the FGFR3 gene were entirely sequenced in a cohort of 25 HCH and one ACH patients in whom common mutations had been excluded. Seven novel missense FGFR3 mutations were identified, one causing ACH and six resulting in HCH. Six of these substitutions were located in the extracellular region and four of them creating additional cysteine residues, were associated with severe phenotypes. No mutations were detected in 19 clinically diagnosed HCH patients. Our results demonstrate that the spectrum of FGFR3 mutations causing short-limb dwarfism is wider than originally recognised and emphasise the requirement for complete screening of the FGFR3 gene if appropriate genetic counselling is to be offered to patients with HCH or ACH lacking the most common mutations and their families.