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: 5.64). 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.

0 Followers
 · 
301 Views
  • Source
    • "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]. "
    American Journal of Medical Genetics Part A 04/2014; 164(4). DOI:10.1002/ajmg.a.36378 · 2.05 Impact Factor
  • Source
    • "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]. "
  • [Show abstract] [Hide abstract]
    ABSTRACT: Barbosa M, Sousa AB, Medeira A, Lourenço T, Saraiva J, Pinto-Basto J, Soares G, Fortuna AM, Superti-Furga A, Mittaz L, Reis-Lima M, Bonafé L. Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population. SLC26A2-related dysplasias encompass a spectrum of diseases: from lethal achondrogenesis type 1B (ACG1B; MIM #600972) and atelosteogenesis type 2 (AO2; MIM #256050) to classical diastrophic dysplasia (cDTD; MIM #222600) and recessive multiple epiphyseal dysplasia (rMED; MIM #226900). This study aimed at characterizing clinically, radiologically and molecularly 14 patients affected by non-lethal SLC26A2-related dysplasias and at evaluating genotype–phenotype correlation. Phenotypically, eight patients were classified as cDTD, four patients as rMED and two patients had an intermediate phenotype (mild DTD – mDTD, previously ‘DTD variant'). The Arg279Trp mutation was present in all patients, either in homozygosity (resulting in rMED) or in compound heterozygosity with the known severe alleles Arg178Ter or Asn425Asp (resulting in DTD) or with the mutation c.727-1G>C (causing mDTD). The ‘Finnish mutation’, c.-26+2T>C, and the p.Cys653Ser, both frequent mutations in non-Portuguese populations, were not identified in any of the patients of our cohort and are probably very rare in the Portuguese population. A targeted mutation analysis for p.Arg279Trp and p.Arg178Ter in the Portuguese population allows the identification of approximately 90% of the pathogenic alleles.
    Clinical Genetics 11/2010; 80(6):550-7. DOI:10.1111/j.1399-0004.2010.01595.x · 3.65 Impact Factor
Show more