Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation.
Human Molecular Genetics
Ashikov A1,2, Abu Bakar N1,2, Wen XY3,4, Niemeijer M1, Rodrigues Pinto Osorio G1, Brand-Arzamendi K3,4, Hasadsri L5, Hansikova H6, Raymond K5, Vicogne D7, Ondruskova N6, Simon MEH8, Pfundt R9, Timal S1,2, Beumers R2, Biot C7, Smeets R2, Kersten M2, Huijben K2; CDG group, Linders PTA10, van den Bogaart G10, van Hijum SAFT11,12, Rodenburg R13, van den Heuvel LP14, van Spronsen F15, Honzik T6, Foulquier F7, van Scherpenzeel M2, Lefeber DJ1,2; CDG group, Mirjam W16, Han B9, Helen M17, Helen M18, Peter VH19, Jiddeke VK20, Diego M21, Lars M22, Katja BH23, Jozef H24, Majid A25, Kevin C26, Johann TWN27.
1 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
2 Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
3 Zebrafish Centre for Advanced Drug Discovery & Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, ON, Canada.
4 Department of Medicine, Physiology & Institute of Medical Science, Faculty of Medicine, University of Toronto, ON, Canada.
5 Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
6 Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
7 CNRS-UMR 8576, Structural and Functional Glycobiology Unit, FRABIO, University of Lille, 59655 Villeneuve d’Ascq, France.
8 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
9 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
10 Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
11 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
12 NIZO, 6710 BA Ede, The Netherlands.
13 Radboud Center for Mitochondrial Disorders, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
14 Department of Pediatrics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
15 Division of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, PO BOX 30.001, 9700 RB Groningen, The Netherlands.
16 Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
17 Centre for Inherited Metabolic Disease, Evelina Children’s Hospital, Guys and St Thomas NHS Foundation Trust, London SE1 7EH, UK.
18 Department of Enzymology and Cellular Function, Institute of Child Health, Athens, Greece.
19 Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
20 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
21 Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Research Hospital, Rome, Italy.
22 Department of Medical Biochemistry, Oslo University Hospital, and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
23 Department of Child Neurology, University Hospital Stavanger, Stavanger, Norway.
24 Department of Paediatrics, Tawam Hospital, Al-Ain, UAE.
25 King Abdullah International Medical Research Centre, King Saud bin Abdul Aziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdul Aziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.
26 NSW Biochemical Genetics Service, The Children’s Hospital at Westmead, Disciplines of Genetic Medicine & Child and Adolescent Health, The University of Sydney, NSW 2145, Australia.
27 Department of Child Health, University Hospital of Wales, Cardiff, UK.
Year of Publication:
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.