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

Rossi, Antonio; Superi-Furga, Andrea

doi:10.1002/humu.1152

Cited by 43 publications

(78 citation statements)

References 30 publications

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“…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%

“…The genotype-phenotype correlation of DTDST mutations has been well described (Superti-Furga et al 1996b;Rossi and Superti-Furga 2001;Karniski 2001Karniski , 2004. The current concept includes homozygotes for null mutations resulting in ACG-1B, heterozygotes for both null and partial-function mutations in either AO-II or DTD, and homozygotes for partial-function mutations in r-MED.…”

Section: Introductionmentioning

confidence: 99%

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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

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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

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Section: Introductionmentioning

confidence: 99%

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

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“…Since the mutation c.2147-2148insCT, common in French descendants, encodes a premature stop codon during translation, this mutation in homozygous cases is related to achondroplasia type 1B. 10 The fetus in the present case was diagnosed with a "classical"…”

Section: Case Reportmentioning

confidence: 72%

“…This genotype suggested that 50% of the protein production had retained its activity, which agrees with data in the literature confirming that individuals with DTD or AO-II (classical) have a mutation in one allele that retains partial activity, with loss of protein function by the other allele. 10,12 As shown in Table 1, there have only been seven case reports of DTD diagnosed by means of prenatal ultrasound. 1,3,15,[17][18][19][20] Moreover, the present case report is only the second in the literature in which prenatal ultrasound and molecular DNA analysis were used for diagnosing DTD.…”

Section: Case Reportmentioning

confidence: 99%

Diastrophic dysplasia: prenatal diagnosis and review of the literature

Honório

Bruns

Gründtner³

et al. 2013

Sao Paulo Med. J.

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CONTEXT: Diastrophic dysplasia is a type of osteochondrodysplasia caused by homozygous mutation in the gene DTDST (diastrophic dysplasia sulfate transporter gene). Abnormalities occurring particularly in the skeletal and cartilaginous system are typical of the disease, which has an incidence of 1 in 100,000 live births. CASE REPORT: The case of a pregnant woman, without any consanguineous relationship with her husband, whose fetus was diagnosed with skeletal dysplasia based on ultrasound findings and DNA tests, is described. An obstetric ultrasound scan produced in the 16 th week of gestation revealed characteristics that guided the clinical diagnosis. Prominent among these characteristics were rhizomelia of the lower and upper limbs (shortening of the proximal portions) and mesomelia (shortening of the intermediate portions). Both upper limbs showed marked curvature, with the first finger of the upper limbs in abduction and clinodactyly of the fifth finger. Molecular analysis using the polymerase chain reaction (PCR) and gene sequencing detected mutations that had already been described in the literature for the gene DTDST, named c.862C > T and c.2147_2148insCT. Therefore, the fetus was a compound heterozygote, carrying two different mutations. CONCLUSIONS: Prenatal diagnosis of this condition allowed a more realistic interpretation of the prognosis, and of the couple's reproductive future. This case report shows the contribution of molecular genetics towards the prenatal diagnosis, for which there are few descriptions in the literature. RESUMOCONTEXTO: A displasia diastrófica é uma osteocondrodisplasia causada por mutação homozigótica no gene DTDST (diastrophic dysplasia sulfate transporter gene). As alterações, principalmente nos sistemas esquelético e cartilaginoso, são típicas dessa doença, que tem uma incidência de 1 em 100.000 nascidos vivos. RELATO DO CASO: Descreve-se o caso de uma mulher gestante, sem relação consanguínea com o seu marido, cujo feto foi diagnosticado com displasia esquelética baseado na ultrassonografia e em testes de DNA. A ultrassonografia obstétrica, realizada na 16 a semana, revelou características que guiaram o diagnóstico clínico. Entre elas, se destacam os membros inferiores e superiores com rizomelia (encurtamento das porções proximais) e mesomelia (encurtamento das porções intermediárias), ambos os membros superiores mostraram acentuada flexão, o primeiro dedo em abdução nas extremidades superiores e clinodactilia do quinto dedo. A análise molecular pela reação em cadeia da polimerase (PCR) e o sequenciamento gênico detectou mutações já descritas na literatura para o gene DTDST, chamado c.862C > T e c.2147_2148insCT. Portanto, o feto é um heterozigoto composto, carreando duas mutações diferentes. CONCLUSÕES: O diagnóstico pré-natal dessa condição permite uma interpretação mais realista do prognóstico e do futuro reprodutivo do casal. Este relato de caso mostra a contribuição da genética molecular no diagnóstico pré-natal, com poucas descrições na literatura.

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“…12 -15 Mutations in this gene can also cause more severe recessive disorders such as achondrogenesis 1B (AGC1B, MIM 600972), atelosteogenesis type 2 (AO2, MIM 256050) and diastrophic dysplasia (DTD, MIM 222600). 16 The homozygous R 279 W mutation is the most common mutation in patients with rMED.…”

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confidence: 99%

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

et al. 2004

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Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes (COMP, COL9A1, COL9A2, COL9A3, MATN3 and DTDST) have been reported, but the genotype -phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by 'mini-epiphyses', resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.

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

Cited by 43 publications

References 30 publications

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

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

Diastrophic dysplasia: prenatal diagnosis and review of the literature

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

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