Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene

Superti‐Furga, Andrea; Hästbacka, Johanna; Wr, Wilcox; Dh, Cohn; Hj, van der Harten; Rossi, Antonio; Blau, Nenad; Dl, Rimoin; Steinmann, Beat; Es, Lander; Gitzelmann, R

doi:10.1038/ng0196-100

Cited by 219 publications

(132 citation statements)

References 12 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…DTDST transports sulfate and contributes to synthesis of sulfated proteoglycans in cartilage. Approximately 40 DTDST mutations have been reported (Rossi and Superti-Furga 2001) in four autosomal recessive chondrodysplasias, including two nonlethal disorders, a recessive form of multiple epiphyseal dysplasia (r-MED) , and diastrophic dysplasia (DTD) (Hastbacka et al 1994); and two lethal disorders, atelosteogenesis type II (AO-II) (Hastbacka et al 1996) and achondrogenesis 1B (ACG-1B) (Superti-Furga et al 1996a). These disorders constitute a disease spectrum termed the diastrophic dysplasia (DTD) group (Lachman 1998;Hall 2002;Superti-Furga et al 2007).…”

Section: Introductionmentioning

confidence: 99%

A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia

et al. 2008

View full text Add to dashboard Cite

Diastrophic dysplasia sulfate transporter (DTDST) is required for synthesis of sulfated proteoglycans in cartilage, and its loss-of-function mutations result in recessively inherited chondrodysplasias. The 40 or so DTDST mutations reported to date cause a group of disorders termed the diastrophic dysplasia (DTD) group. The group ranges from the mildest recessive form of multiple epiphyseal dysplasia (r-MED) through the most common DTD to perinatally lethal atelosteogenesis type II and achondrogenesis 1B. Furthermore, the relationship between DTDST mutations, their sulfate transport function, and disease phenotypes has been described. Here we report a girl with DTDST mutations: a compound heterozygote of a novel p.T266I mutation and a recurrent p.DV340 mutation commonly found in severe phenotypes of the DTD group. In infancy, the girl presented with skeletal manifestations reminiscent of Desbuquois dysplasia, another recessively inherited chondrodysplasia, the mutations of which have never been identified. Her phenotype evolved with age into an intermediate phenotype between r-MED and DTD. Considering her clinical phenotypes and known phenotypes of p.DV340, p.T266I was predicted to be responsible for mild phenotypes of the DTD group. Our results further extend the phenotypic spectrum of DTDST mutations, adding Desbuquois dysplasia to the list of differential diagnosis of the DTD group.Keywords Diastrophic dysplasia sulfate transporter (DTDST) Á Diastrophic dysplasia (DTD) Á Recessive form of multiple epiphyseal dysplasia (r-MED) Á Desbuquois dysplasia Á Genotype-phenotype correlation

show abstract

Section: Introductionmentioning

confidence: 99%

A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia

et al. 2008

View full text Add to dashboard Cite

show abstract

“…We subsequently showed that DTDST mutations also underlie two other chondrodysplasias: atelosteogenesis type II (AOII) 3 and achondrogenesis type IB (ACG1B), 4 both of which are recessive and perinatally lethal. DTDST mutations thus give rise to a clinical spectrum, with compound heterozygosity and mutational overlap observed: several mutations have been detected in two or three of the conditions.…”

Section: Introductionmentioning

confidence: 99%

“…DTDST mutations thus give rise to a clinical spectrum, with compound heterozygosity and mutational overlap observed: several mutations have been detected in two or three of the conditions. [3][4][5][6][7] The severity of the phenotype appears to correlate with residual DTDST function, although additional factors can also influence expression as illustrated by intrafamilial phenotypic variability. 8,9 Despite extensive characterization of DTDST mutations, we had previously been unable to identify the major founder mutation accounting for the high prevalence of DTD in the Finnish population.…”

Section: Introductionmentioning

confidence: 99%

Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)

et al. 1999

Self Cite

View full text Add to dashboard Cite

Diastrophic dysplasia (DTD) is especially prevalent in Finland and the existence of a founder mutation has been previously inferred from the fact that 95% of Finnish DTD chromosomes have a rare ancestral haplotype found in only 4% of Finnish control chromosomes. Here we report the identification of the Finnish founder mutation as a GT-> GC transition (c.-26 + 2T > C) in the splice donor site of a previously undescribed 5'-untranslated exon of the diastrophic dysplasia sulfate transporter gene (DTDST); the mutation acts by severely reducing mRNA levels. Among 84 DTD families in Finland, patients carried two copies of the mutation in 69 families, one copy in 14 families, and no copies in one family. Roughly 90% of Finnish DTD chromosomes thus carry the splice-site mutation, which we have designated DTDST Fin . Unexpectedly, we found that nine of the DTD chromosomes having the apparently ancestral haplotype did not carry DTDST Fin , but rather two other mutations. Eight such chromosomes had an R279W mutation and one had a V340del deletion. We consider the possible implications of presence of multiple DTD mutations on this rare haplotype.

show abstract

“…The major catalytic machinery responsible for the biosynthesis and breakage of sulfate esters in the proteoglycans is composed of various enzymes and transporters. Mutations in genes encoding the transmembrane transporters of sulfate or enzymes involved in the synthesis of PAPS have been identified as the causes for several inherited diseases that all show deformities in the skeletal system [6][7][8]. Moreover, several studies also showed that genetic defects in genes encoding the sulfatases disturb the sulfate metabolism and result in some human inherited diseases.…”

Section: Dear Editormentioning

confidence: 99%