1. Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation
- Author
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Angel, Ashikov, Nurulamin, Abu Bakar, Xiao-Yan, Wen, Marco, Niemeijer, Glentino, Rodrigues Pinto Osorio, Koroboshka, Brand-Arzamendi, Linda, Hasadsri, Hana, Hansikova, Kimiyo, Raymond, Dorothée, Vicogne, Nina, Ondruskova, Marleen E H, Simon, Rolph, Pfundt, Sharita, Timal, Roel, Beumers, Christophe, Biot, Roel, Smeets, Marjan, Kersten, Karin, Huijben, Peter T A, Linders, Geert, van den Bogaart, Sacha A F T, van Hijum, Richard, Rodenburg, Lambertus P, van den Heuvel, Francjan, van Spronsen, Tomas, Honzik, Francois, Foulquier, Monique, van Scherpenzeel, Dirk J, Lefeber, Wamelink, Mirjam, Brunner, Han, Mundy, Helen, Michelakakis, Helen, van Hasselt, Peter, van de Kamp, Jiddeke, Martinelli, Diego, Morkrid, Lars, Brocke Holmefjord, Katja, Hertecant, Jozef, Alfadhel, Majid, Carpenter, Kevin, Te Water Naude, Johann, Center for Liver, Digestive and Metabolic Diseases (CLDM), Department of Medicine & Physiology , University of Toronto, First Faculty of Medicine, Charles University [Prague] (CU), Université Lille Nord de France (COMUE), University Medical Center [Utrecht], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Unité de Catalyse et Chimie du Solide - UMR 8181 (UCCS), Centrale Lille Institut (CLIL)-Université d'Artois (UA)-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Lille, Paediatrics, Beatrix Children's Hospital/University Medical Center Groningen, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Charles University [Prague], Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, NCA - Brain mechanisms in health and disease, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
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Male ,0301 basic medicine ,N-GLYCAN ,HOMEOSTASIS ,Glycosylation ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,[SDV]Life Sciences [q-bio] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Golgi Apparatus ,Compound heterozygosity ,DISEASE ,Cohort Studies ,Congenital Disorders of Glycosylation ,Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase ,Missense mutation ,Genetics(clinical) ,Exome ,Glycomics ,Zebrafish ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,Genetics (clinical) ,Genetics & Heredity ,chemistry.chemical_classification ,SEVERE INTELLECTUAL DISABILITY ,Symporters ,biology ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Genomics ,General Medicine ,DEFECTS ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Pedigree ,Cell biology ,Transport protein ,DEFICIENCY ,Protein Transport ,Phenotype ,symbols ,Female ,ENAMEL ,Life Sciences & Biomedicine ,Adult ,Biochemistry & Molecular Biology ,DISORDERS ,Organic Anion Transporters, Sodium-Dependent ,PHENOTYPES ,DIAGNOSIS ,TRANSFERRIN ,Young Adult ,03 medical and health sciences ,symbols.namesake ,All institutes and research themes of the Radboud University Medical Center ,Calcification, Physiologic ,Genetics ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,BIOSYNTHESIS ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,Bone Diseases, Developmental ,Science & Technology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MUTATIONS ,Infant ,Heterozygote advantage ,Fibroblasts ,Golgi apparatus ,biology.organism_classification ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,chemistry ,Mutation ,Glycoprotein - Abstract
Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix. ispartof: HUMAN MOLECULAR GENETICS vol:27 issue:17 pages:3029-3045 ispartof: location:England status: published
- Published
- 2018
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