Exome Sequencing Reveals a Phenotype Modifying Variant in ZNF528 in Primary Osteoporosis With a COL1A2 Deletion
| Autor: | Outi Mäkitie, Minna Männikkö, Jihan Xia, Alice Costantini, Sini Skarp, Gong-Hong Wei, Qin Zhang, Lloyd W. Ruddock, Marika Löija |
|---|---|
| Přispěvatelé: | HUS Children and Adolescents, Clinicum, Lastentautien yksikkö, Children's Hospital, University of Helsinki, Helsinki University Hospital Area, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Candidate gene COL1A2 PRIMARY OSTEOPOROSIS Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Biology Collagen Type I 03 medical and health sciences EXOME SEQUENCING 0302 clinical medicine medicine Humans Exome HETEROGENEITY Orthopedics and Sports Medicine TRANSCRIPTION FACTOR TRANSCRIPTION MUTATION Gene Transcription factor Exome sequencing Sequence Deletion 2. Zero hunger Genetics ZNF528 Wild type Original Articles medicine.disease Phenotype 030104 developmental biology OSTEOGENESIS IMPERFECTA 3121 General medicine internal medicine and other clinical medicine Osteoporosis Original Article LETHAL VARIANT COL1A2 GENE BONE Haploinsufficiency EHLERS-DANLOS-SYNDROME FORM Bruck syndrome Transcription Factors BRUCK-SYNDROME |
| Zdroj: | Journal of Bone and Mineral Research |
| ISSN: | 1523-4681 0884-0431 |
| DOI: | 10.1002/jbmr.4145 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text