PHENOTYPIC AND GENOTYPIC OVERLAP BETWEEN ATELOSTEOGENESIS TYPE-2 AND DIASTROPHIC DYSPLASIA

Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias that comprises , in order of increasing severity, diastrophic dysplasia (DTD), atelos teogenesis type 2 (AO2), and achondrogenesis type 1B (ACG1B), To learn more about the molecular basis of DTDST chondrodysplasias and about g enotype-phenotype correlations, we studied fibroblast cultures of thre e new patients: one with AO-2, one with DTD, and one with an intermedi ate phenotype (AO2/DTD). Reduced incorporation of inorganic sulfate in to macromolecules was found in all three, Each of the three patients w as found to be heterozygous for a c862t transition predicting a R279W substitution in the third extracellular loop of DTDST. In two patients (DTD and AO2/DTD), no other structural mutation was found, but polyme rase chain reaction amplification and single-strand conformation polym orphism analysis of fibroblast cDNA showed reduced mRNA levels of the wild-type DTDST allele: these two patients may be compound heterozygot es for the ''Finnish'' mutation (as yet uncharacterized at the DNA lev el), which causes reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the del etion of cytosine 418 (Delta c418), predicting a frameshift with prema ture termination. Also the Delta c418 allele was underrepresented in t he cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R279W mutation in a total of 11 patients with AO2 or DTD emphasizes the overlap between these conditions. This mutation has not been found so far in 8 analyz ed ACG1B patients, suggesting that it allows some residual activity of the sulfate transporter.