University of Oulu

Skarp, S., Xia, J.‐H., Zhang, Q., Löija, M., Costantini, A., Ruddock, L.W., Mäkitie, O., Wei, G.‐H. and Männikkö, M. (2020), Exome Sequencing Reveals a Phenotype Modifying Variant in ZNF528 in Primary Osteoporosis With a COL1A2 Deletion. J Bone Miner Res, 35: 2381-2392.

Exome sequencing reveals a phenotype modifying variant in ZNF528 in primary osteoporosis with a COL1A2 deletion

Saved in:
Author: Skarp, Sini1,2,3; Xia, Ji‐Han2,4; Zhang, Qin2,4;
Organizations: 1Infrastructure for Population Studies, Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
4Biocenter Oulu, University of Oulu, Oulu, Finland
5Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet/Stockholm, Stockholm, Sweden
6Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
7Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
8Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland
9Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
10Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
Persistent link:
Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2021-01-22


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.

see all

Series: Journal of bone and mineral research
ISSN: 0884-0431
ISSN-E: 1523-4681
ISSN-L: 0884-0431
Volume: 35
Issue: 12
Pages: 2381 - 2392
DOI: 10.1002/jbmr.4145
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Funding: This study was financially supported by the University of Oulu (university researcher recruitment funding), Academy of Finland (277843), the Sigrid Jusélius Foundation, the Folkhälsan Research Foundation and the Novo Nordisk Foundation (21322), and the Swedish Research Council (2018-02645).
Copyright information: © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.