Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation

CDG Group

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3029-3045
Number of pages17
JournalHuman Molecular Genetics
Volume27
Issue number17
DOIs
Publication statusPublished - Sep 1 2018

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Glycomics
Physiologic Calcification
Protein Transport
Genomics
Glycosylation
Glycoproteins
Zebrafish
Amelogenesis Imperfecta
Exome
Phenotype
RNA Splice Sites
Mutation
Missense Mutation
Bone Density
Osteoporosis
Extracellular Matrix
Polysaccharides
Cluster Analysis
Cell Biology
Siblings

Cite this

@article{e5f9646ae54d4fa1b3348ec0b573133e,
title = "Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation",
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.",
author = "{CDG Group} and Angel Ashikov and {Abu Bakar}, Nurulamin and Xiao-Yan Wen and Marco Niemeijer and {Rodrigues Pinto Osorio}, Glentino and Koroboshka Brand-Arzamendi and Linda Hasadsri and Hana Hansikova and Kimiyo Raymond and Doroth{\'e}e Vicogne and Nina Ondruskova and Simon, {Marleen E H} and Rolph Pfundt and Sharita Timal and Roel Beumers and Christophe Biot and Roel Smeets and Marjan Kersten and Karin Huijben and Linders, {Peter T A} and {van den Bogaart}, Geert and {van Hijum}, {Sacha A F T} and Richard Rodenburg and {van den Heuvel}, {Lambertus P} and {van Spronsen}, Francjan and Tomas Honzik and Francois Foulquier and {van Scherpenzeel}, Monique and Lefeber, {Dirk J} and Wamelink Mirjam and Brunner Han and Mundy Helen and Michelakakis Helen and Peter, {van Hasselt} and Jiddeke, {van de Kamp} and Martinelli Diego and Morkrid Lars and Katja, {Brocke Holmefjord} and Hertecant Jozef and Alfadhel Majid and Carpenter Kevin and Johann, {Te Water Naude}",
year = "2018",
month = "9",
day = "1",
doi = "10.1093/hmg/ddy213",
language = "English",
volume = "27",
pages = "3029--3045",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "17",

}

TY - JOUR

T1 - Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation

AU - CDG Group

AU - Ashikov, Angel

AU - Abu Bakar, Nurulamin

AU - Wen, Xiao-Yan

AU - Niemeijer, Marco

AU - Rodrigues Pinto Osorio, Glentino

AU - Brand-Arzamendi, Koroboshka

AU - Hasadsri, Linda

AU - Hansikova, Hana

AU - Raymond, Kimiyo

AU - Vicogne, Dorothée

AU - Ondruskova, Nina

AU - Simon, Marleen E H

AU - Pfundt, Rolph

AU - Timal, Sharita

AU - Beumers, Roel

AU - Biot, Christophe

AU - Smeets, Roel

AU - Kersten, Marjan

AU - Huijben, Karin

AU - Linders, Peter T A

AU - van den Bogaart, Geert

AU - van Hijum, Sacha A F T

AU - Rodenburg, Richard

AU - van den Heuvel, Lambertus P

AU - van Spronsen, Francjan

AU - Honzik, Tomas

AU - Foulquier, Francois

AU - van Scherpenzeel, Monique

AU - Lefeber, Dirk J

AU - Mirjam, Wamelink

AU - Han, Brunner

AU - Helen, Mundy

AU - Helen, Michelakakis

AU - Peter, van Hasselt

AU - Jiddeke, van de Kamp

AU - Diego, Martinelli

AU - Lars, Morkrid

AU - Katja, Brocke Holmefjord

AU - Jozef, Hertecant

AU - Majid, Alfadhel

AU - Kevin, Carpenter

AU - Johann, Te Water Naude

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddy213

DO - 10.1093/hmg/ddy213

M3 - Article

C2 - 29878199

VL - 27

SP - 3029

EP - 3045

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 17

ER -