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A novel mutation in the sulphate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia.
  1. Luisa Bonafé (luisa.bonafe{at}chuv.ch)
  1. Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
    1. Johanna Hastbacka (johanna.hastbacka{at}helsinki.fi)
    1. Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, Finland
      1. Albert de la Chapelle (albert.delachapelle{at}osumc.edu)
      1. Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States
        1. Ana Belinda Campos-Xavier (belinda.xavier{at}chuv.ch)
        1. Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
          1. Carole Chiesa (carole.chiesa{at}chuv.ch)
          1. Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
            1. Antonella Forlino (aforlino{at}unipv.it)
            1. Department of Biochemistry “Alessandro Castellani”, University of Pavia, Italy
              1. Andrea Superti-Furga (asuperti{at}uniklinik-freiburg.de)
              1. Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Germany
                1. Antonio Rossi (antrossi{at}unipv.it)
                1. Department of Biochemistry “Alessandro Castellani”, University of Pavia, Italy

                  Abstract

                  Background: Mutations in the sulphate transporter gene SLC26A2 (DTDST) cause a continuum of skeletal dysplasia phenotypes that includes achondrogenesis type1B (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.

                  Objective: To test the hypothesis whether SLC26A2 mutations are responsible for DLCD.

                  Methods: We studied the DNA from the original DLCD family and from 7 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 sulphate transport deficient Chinese Hamster ovary (CHO) cells to measure sulphate uptake activity.

                  Results: 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.

                  Conclusions: 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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