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Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases
  1. Tatsuya Furuichi (furuichi{at}src.riken.jp)
  1. Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Japan
    1. Hulya Kayserili
    1. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Turkey
      1. Shuichi Hiraoka
      1. Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Japan
        1. Gen Nishimura
        1. Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Japan
          1. Hirofumi Ohashi
          1. Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan
            1. Yasemin Alanay
            1. Dept of Pediatrics, Ihsan Dogramaci Children's Hospital, Hacettepe University School of Medicine, Turkey
              1. JC Llerena, Jr
              1. Medical Genetic Center, Instituto Fernandes Figueira, Brazil
                1. Ayca D Aslanger
                1. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Japan
                  1. Haruhiko Koseki
                  1. Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Japan
                    1. Daniel H Cohn
                    1. Medical Genetics Research Institute, Cedars-Sinai Medical Center, LA, United States
                      1. Andrea Superti-Furga
                      1. Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Germany
                        1. Sheila Unger
                        1. Centre for Pediatrics and Adolescent Medincine & Institute for Human Genetics, Univ of Freiburg, Germany
                          1. Shiro Ikegawa (sikegawa{at}ims.u-tokyo.ac.jp)
                          1. Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Japan

                            Abstract

                            Background:Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD.

                            Object: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group.

                            Methods and results: We searched for SLC35D1 mutations in five families with SBD and fifteen patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15) and c.193A>C (p. T65P) in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a fameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide-sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases.

                            Conclusion: Our findings suggest that SLC35D1 loss of function mutations result consistently in SBD and are exclusive to SBD.

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