title: Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype.
abstract: The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include diastrophic dysplasia, multiple epiphyseal dysplasia, atelosteogenesis type 2 and achondrogenesis 1B (ACG-1B). To determine whether the DTDST mutations found in individuals with these chondrodysplasias differ functionally from each other, we compared the sulfate transport activity of 11 reported DTDST mutations. Five mutations, G255E, Delta a1751, L483P, R178X and N425D, had minimal sulfate transport function following expression in Xenopus laevis oocytes. Two mutations, Delta V340 and R279W, transported sulfate at rates of 17 and 32%, respectively, of wild-type DTDST. Four mutations, A715V, C653S, Q454P and G678V, had rates of sulfate transport nearly equal to that of wild-type DTDST. Transport kinetics were not different among the four mutations with near-normal sulfate transport function and wild-type DTDST. When the sulfate transport function of the different DTDST mutations are grouped according to the general phenotypes, individuals with the most severe form, ACG-1B, tend to be homozygous for null mutations, individuals with the moderately severe atelosteogenesis type 2 have at least one allele with a loss-of-function mutation, and individuals with the mildest forms are typically homozygous for mutations with residual sulfate transport function. However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.
authors.affiliation: Laboratory of Epithelial Transport, Department of Internal Medicine, Veterans Affairs Medical Center and University of Iowa College of Medicine, Iowa City, IA 52242, USA. lawrence-karniski@uiowa.edu
authors.forename: L P
authors.initials: LP
authors.lastname: Karniski
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D026901:Membrane Transport Proteins; D009154:Mutation; D009865:Oocytes; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000493:pharmacokinetics; D013223:Statistics as Topic; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D011509:Proteoglycans; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters; D013431:Sulfates; D012964:Sodium