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.
| Original language | English |
|---|---|
| Pages (from-to) | 678-691 |
| Number of pages | 14 |
| Journal | Journal of Bone and Mineral Research |
| Volume | 38 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 23 Feb 2023 |
Bibliographical note
Funding Information:AOGC investigators include 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 was 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 Ref. 511132). Funding was also received from the Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). 1 2 1 3 4,5 6 7 8 9 2
Funding Information:
AOGC investigators include Eugene McCloskey,1 Geoffrey C. Nicholson,2 Richard Eastell,1 Richard L. Prince,3 John A. Eisman,4,5 Graeme Jones,6 Philip Sambrook7 (deceased), Ian R. Reid,8 Elaine M. Dennison,9 and John Wark.2 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 was 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 Ref. 511132). Funding was also received from the Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). 1University of Sheffield, UK, 2University of Melbourne, Geelong, Australia, 3University of Western Australia, Perth, Australia, 4St Vincent's Clinical School, University of New South Wales, 5Menzies Research Institute, University of Tasmania, Hobart, Australia, 6Kolling Institute, Royal North Shore Hospital, University of Sydney, Australia, 7University of Auckland, New Zealand, 8Medical Research Council Resource Centre, Southampton, UK.
Publisher Copyright:
© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).