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Hassan, Neelam, Gregson, Celia L., Tang, Haotian, van der Kamp, Marc W., Leo, Paul, McInerney-Leo, Aideen M., Zheng, Jie, Brandi, Maria Luisa, Tang, Jonathan C. Y. 
ORCID: https://orcid.org/0000-0001-6305-6333, Fraser, William, Stone, Michael D., Grundberg, Elin, Brown, Matthew A., Duncan, Emma L. and Tobias, Jonathan H.
and
Anglo-Australasian Genetics Consortium
(2023)
Rare and common variants in GALNT3 may affect bone mass independently of phosphate metabolism.
Journal of Bone and Mineral Research, 38 (5).
pp. 678-691.
ISSN 0884-0431
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Abstract
Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C>T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831T>A, p.Asp277Glu) within the same gene. In silico protein modelling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3; and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or co-receptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and GWAS data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, identification of which may yield novel anabolic drug targets for osteoporosis.
| Item Type: | Article |
|---|---|
| Additional Information: | Peer Review: The peer review history for this article is available at https://publons.com/publon/10.1002/jbmr.4795. Acknowledgements: AOGC investigators comprise: Eugene McCloskey, Geoffrey C Nicholson, Richard Eastell, Richard L Prince, John A Eisman, Graeme Jones, Philip Sambrook (deceased), Ian R Reid, Elaine M Dennison and John Wark. NH was supported by the Medical Research Council (MR/V00199X/1), Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (8064/Hassan/WT ISSF 3). CLG was funded by the Wellcome Trust (080280/Z/06/Z), the EU 7th Framework Programme ref 247642 (GEoCoDE), a British Geriatric Society travel grant, and Versus Arthritis (formerly Arthritis Research UK) (grant ref 20000). MAB was funded by a National Health and Medical Research Council (Australia) Principal Research Fellowship. ELD was funded by a National Health and Medical Research Council (Australia) Career Development Award (569807). AML is funded by a National Health and Medical Research Council Early Career Fellowship (APP1158111). The AOGC was funded by the National Health and Medical Research Council (Australia) (grant reference 511132). Funding was also received from the Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). |
| Uncontrolled Keywords: | exome sequencing,galnt3,high bone mass,monogenic,phosphate,endocrinology, diabetes and metabolism,orthopedics and sports medicine ,/dk/atira/pure/subjectarea/asjc/2700/2712 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 08 Mar 2023 12:30 |
| Last Modified: | 19 Oct 2023 03:34 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/91444 |
| DOI: | 10.1002/jbmr.4795 |
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