Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 Novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance

Mutations in the DTDST gene can result in a family of skeletal dysplasia co nditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1 B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastro phic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). Th e gene product is a sulfate-chloride exchanger of the cell membrane. Inacti vation of the sulfate exchanger leads to intracellular sulfate depletion an d to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recog nizable, with mutations predicting a truncated protein or a non-conservativ e amino acid substitution in a transmembrane domain giving the severe pheno types, and non transmembrane amino acid substitutions and splice site mutat ions giving the milder phenotypes. The clinical phenotype is modulated stri ctly by the degree of residual activity. Over 30 mutations have been observ ed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygo us and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence, Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It pro duces low levels of correctly spliced mRNA, and results in DTD when homozyg ous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patie nts. Most other mutations are rare. Heterozygotes are clinically unaffected . When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/ DTD/rMED spectrum prior to analysis, the mu tation detection rate is high (over 90% of alleles), and appropriate geneti c counseling can be given. The sulfate uptake or sulfate incorporation as s ays in cultured fibroblasts have largely been replaced by mutation analysis , but may still be useful in cases where mutation analysis is not informati ve. Although supplementation of patients' cultured cells with thiols may by pass the transporter defect and enhance sulfation of proteoglycans, therape utic approaches are not yet available. Mouse models for this and other diso rders of sulfate metabolism are being developed to help in developing thera peutic treatments. Hum Mutat 17:159-171, 2001. (C) 2001 Wiley-Liss, Inc.