Article

A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia

Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Journal of Medical Genetics (Impact Factor: 6.34). 08/2008; 45(12):827-31. DOI: 10.1136/jmg.2007.057158
Source: PubMed

ABSTRACT

Mutations in the sulfate transporter gene SLC26A2 (DTDST) cause a continuum of skeletal dysplasia phenotypes that includes achondrogenesis type 1B (ACG1B), atelosteogenesis type 2 (AO2), diastrophic dysplasia (DTD), and recessive multiple epiphyseal dysplasia (rMED). In 1972, de la Chapelle et al reported two siblings with a lethal skeletal dysplasia, which was denoted "neonatal osseous dysplasia" and "de la Chapelle dysplasia" (DLCD). It was suggested that DLCD might be part of the SLC26A2 spectrum of phenotypes, both because of the Finnish origin of the original family and of radiographic similarities to ACG1B and AO2.
To test the hypothesis whether SLC26A2 mutations are responsible for DLCD.
We studied the DNA from the original DLCD family and from seven Finnish DTD patients in whom we had identified only one copy of IVS1+2T>C, the common Finnish mutation. A novel SLC26A2 mutation was found in all subjects, inserted by site-directed mutagenesis in a vector harbouring the SLC26A2 cDNA, and expressed in sulfate transport deficient Chinese hamster ovary (CHO) cells to measure sulfate uptake activity.
We identified a hitherto undescribed SLC26A2 mutation, T512K, homozygous in the affected subjects and heterozygous in both parents and in the unaffected sister. T512K was then identified as second pathogenic allele in the seven Finnish DTD subjects. Expression studies confirmed pathogenicity.
DLCD is indeed allelic to the other SLC26A2 disorders. T512K is a second rare "Finnish" mutation that results in DLCD at homozygosity and in DTD when compounded with the milder, common Finnish mutation.

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    • "The four most common SCL26A2 mutations, which account for 70% of disease alleles (66% in DTD cases and 90% in EDM4/rMED cases) are: p.Arg279Trp which is the most common mutation in non-Finnish patients [Superti-Furga et al., 1999], c.-26þ2T>C (also known as " Finnish allele " ), p.Arg178Ter and p.Cys653Ser [Bonafé et al., 2008]. The SLC26A2 gene encodes a sulfate transporter that consists of a 5 0 untranslated exon with regulatory functions and two coding exons that play a crucial role for the uptake of inorganic sulfate into chondrocytes in order to maintain adequate levels of intracellular sulfate and allow proper sulfation of the proteoglycans [Forlino et al., 2005]. "

    Full-text · Article · Apr 2014 · American Journal of Medical Genetics Part A
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    • "The four most common SCL26A2 mutations, which account for 70% of disease alleles (66% in DTD cases and 90% in EDM4/rMED cases) are: p.Arg279Trp which is the most common mutation in non-Finnish patients [Superti-Furga et al., 1999], c.-26þ2T>C (also known as " Finnish allele " ), p.Arg178Ter and p.Cys653Ser [Bonafé et al., 2008]. The SLC26A2 gene encodes a sulfate transporter that consists of a 5 0 untranslated exon with regulatory functions and two coding exons that play a crucial role for the uptake of inorganic sulfate into chondrocytes in order to maintain adequate levels of intracellular sulfate and allow proper sulfation of the proteoglycans [Forlino et al., 2005]. "

    Full-text · Dataset · Jan 2014
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    • "Mutations in other genes of the sulfation cascade, such as chondroitin-4-sulfotransferase 1 (Chst11) [45], diastropic dysplasia transporter (Dtdst or Slc26a2) [46,47] and extracellular heparan endosulfatases (Sulf-1 and Sulf-2) [48], have also been shown to result in various types of chondrodysplasias, some of which are lethal (mutations in Dtdst: achondrogenesis type IB [OMIM:600972]; atelosteogenesis type 2 [OMIM:256050]). Chst11 was recently identified as a target of bone morphogenetic protein (BMP) signaling and also was found to contain cis-regulatory modules that potentially could respond to TGF-β. "
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