Exome Sequencing Reveals a Phenotype Modifying Variant inZNF528in Primary Osteoporosis With aCOL1A2Deletion

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Skarp , S , Xia , J-H , Zhang , Q , Löija , M , Costantini , A , Ruddock , L W , Mäkitie , O , Wei , G-H & Männikkö , M 2020 , ' Exome Sequencing Reveals a Phenotype Modifying Variant inZNF528in Primary Osteoporosis With aCOL1A2Deletion ' , Journal of Bone and Mineral Research , vol. 35 , no. 12 , pp. 2381-2392 . https://doi.org/10.1002/jbmr.4145

Title: Exome Sequencing Reveals a Phenotype Modifying Variant inZNF528in Primary Osteoporosis With aCOL1A2Deletion
Author: Skarp, Sini; Xia, Ji-Han; Zhang, Qin; Löija, Marika; Costantini, Alice; Ruddock, Lloyd W.; Mäkitie, Outi; Wei, Gong-Hong; Männikkö, Minna
Contributor organization: HUS Children and Adolescents
Lastentautien yksikkö
Children's Hospital
University of Helsinki
Helsinki University Hospital Area
CAMM - Research Program for Clinical and Molecular Metabolism
Faculty of Medicine
Date: 2020-12
Language: eng
Number of pages: 12
Belongs to series: Journal of Bone and Mineral Research
ISSN: 0884-0431
DOI: https://doi.org/10.1002/jbmr.4145
URI: http://hdl.handle.net/10138/323379
Abstract: We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2, leading to haploinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype. We hypothesized that other genetic factors may contribute to the severe phenotype in this family. We performed whole-exome sequencing in five family members and identified in all three affected individuals a rare nonsense variant (c.1282C > T/p.Arg428*, rs150257846) in ZNF528. We studied the effect of the variant using qPCR and Western blot and its subcellular localization with immunofluorescence. Our results indicate production of a truncated ZNF528 protein that locates in the cell nucleus as per the wild-type protein. ChIP and RNA sequencing analyses on ZNF528 and ZNF528-c.1282C > T indicated that ZNF528 binding sites are linked to pathways and genes regulating bone morphology. Compared with the wild type, ZNF528-c.1282C > T showed a global shift in genomic binding profile and pathway enrichment, possibly contributing to the pathophysiology of primary osteoporosis. We identified five putative target genes for ZNF528 and showed that the expression of these genes is altered in patient cells. In conclusion, the variant leads to expression of truncated ZNF528 and a global change of its genomic occupancy, which in turn may lead to altered expression of target genes. ZNF528 is a novel candidate gene for bone disorders and may function as a transcriptional regulator in pathways affecting bone morphology and contribute to the phenotype of primary osteoporosis in this family together with the COL1A2 deletion. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion

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