Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia

Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dys plasias characterized by disproportionate short stature. The diagnosis of t hese conditions might be difficult to establish especially in early childho od, Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhiz omelic body disproportion, whereas mutations in the fibroblast growth facto r receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in f ive DCO and 18 HCH patients, all of whom tested negative for the known HCH- associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequ encing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients wa s carefully determined. Three novel mutations in DCO patients were found: ( 1) a deletion of one base (del272G) (according to GenBank accession nos. Y1 1536, Y11535), resulting in a premature stop codon at position 75 of the am ino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitutio n. These substitutions segregate with the DCO phenotype and affect evolutio narily conserved homeodomain residues, based on a comparison of homeobox co ntaining proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mut ations are pathogenic. The phenotype of our patients with DCO and HCH varie d from mild to severe shortness and body disproportion. These results furth er support clinical and genetic heterogeneity of dyschondrosteosis and hypo chondroplasia.