Rare and common variants in <em>GALNT3</em> may affect bone mass independently of phosphate metabolism

Hassan, Neelam; Gregson, Celia L.; Tang, Haotian; van der Kamp, Marc; Leo, Paul; McInerney-Leo, Aideen M.; Zheng, Jie; Brandi, Maria Luisa; Tang, Jonathan C. Y.; Fraser, William; Stone, Michael D.; Grundberg, Elin; Brown, Matthew A.; Duncan, Emma L.; Tobias, Jonathan H.

Affiliations

¹Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

²MRC Integrated Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

³School of Biochemistry, University of Bristol, Bristol, UK

⁴Faculty of Health, Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

⁵The Faculty of Medicine, Frazer Institute, The University of Queensland, Woolloongabba, Queensland, Australia

⁶Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁷Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁸Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

⁹FIRMO Foundation, Florence, Italy

¹⁰Norwich Medical School, University of East Anglia, Norwich, UK

¹¹Clinical Biochemistry, Departments of Laboratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK

¹²Department of Diabetes, Endocrinology and Clinical Biochemistry, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK

¹³University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff, UK

¹⁴Genomic Medicine Center, Children’s Mercy Kansas City, Kansas City, Missouri, USA

¹⁵Genomics England, London, UK

¹⁶Department of Twin Research and Genetic Epidemiology, School of Life Course & Population Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK

Abstract and keywords

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.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling 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 coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies 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, the identification of which may yield novel anabolic drug targets for osteoporosis.

Keywords: HIGH BONE MASS; EXOME SEQUENCING; MONOGENIC; GALNT3; PHOSPHATE

Links

DOI: 10.1002/jbmr.4795

PubMed: 36824040

WoS: 000948636100001

History

Received: 2022-09-19

Revised: 2023-02-15

Accepted: 2023-02-22

Cited Works (12)

Year	Entry
1997	Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D; European Foundation for Osteoporosis and Bone Disease. Guidelines for diagnosis and management of osteoporosis. Osteoporos Int. July 1997;7(4):390-406.
2002	Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor–related protein 5. NEJM. May 16, 2002;346(20):1513-1521.
2001	Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo P, Fu Y-H, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan JT. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot–containing protein. Am J Hum Genet. March 2001;68(3):577-589.
2021	Ito N, Fukumoto S. Congenital hyperphosphatemic conditions caused by the deficient activity of FGF23. Calcif Tiss Int. January 2021;108(1):104-115.
2020	Gregson CL, Bergen DJM, Leo P, Sessions RB, Wheeler L, Hartley A, Youlten S, Croucher PI, McInerney‐Leo AM, Fraser W, Tang JCY, Anderson L, Marshall M, Sergot L, Paternoster L, Smith GD, Brown MA, Hammond C, Kemp JP, Tobias JH, Duncan EL; The AOGC Consortium. A rare mutation in SMAD9 associated with high bone mass identifies the SMAD‐dependent BMP signaling pathway as a potential anabolic target for osteoporosis. J Bone Miner Res. January 2020;35(1):92-105.
2012	Estrada K, Styrkarsdottir U, Evangelou E, Hsu Y-H, Duncan EL, Ntzani EE, Oei L, Albagha OME, Amin N, Kemp JP, Koller DL, Li G, Liu C-T, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao S-M, Yerges-Armstrong LM, Zheng H-F, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh J-M, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NLS, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JBJ, Verlaan D, Williams FMK, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw K-T, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HAP, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AWC, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JPA, Kiel DP, Rivadeneira F. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. April 15, 2012;44(5):491-501.
2014	McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster J-Y, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang Y-C, Libanati C, Bone HG. Romosozumab in postmenopausal women with low bone mineral density. NEJM. January 30, 2014;370(5):412-420.
2007	Burge R, Dawson‐Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis‐related fractures in the United States, 2005–2025. J Bone Miner Res. March 2007;22(3):465-475.
2017	Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum A-T, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DM. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. October 2017;49(10):1468-1475.
2020	Koller G, Goetz V, Vandermeer B, Homik J, McAlister FA, Kendler D, Ye C. Persistence and adherence to parenteral osteoporosis therapies: a systematic review. Osteoporos Int. November 2020;31(11):2093-2102.
2019	Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, Sergio CM, Quinn J, Nguyen-Yamamoto L, Luco A-L, Vijay J, Simon M-M, Pramatarova A, Medina-Gomez C, Trajanoska K, Ghirardello EJ, Butterfield NC, Curry KF, Leitch VD, Sparkes PC, Adoum A-T, Mannan NS, Komla-Ebri DSK, Pollard AS, Dewhurst HF, Hassall TAD, Beltejar M-JG; 23andMe Research Team, Adams DJ, Vaillancourt SM, Kaptoge S, Baldock P, Cooper C, Reeve J, Ntzani EE, Evangelou E, Ohlsson C, Karasik D, Rivadeneira F, Kiel DP, Tobias JH, Gregson CL, Harvey NC, Grundberg E, Goltzman D, Adams DJ, Lelliott CJ, Hinds DA, Ackert-Bicknell CL, Hsu Y-H, Maurano MT, Croucher PI, Williams GR, Bassett JHD, Evans DM, Richards JB. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. February 2019;51(2):258-266.
2020	Kiel DP, Kemp JP, Rivadeneira F, Westendorf JJ, Karasik D, Duncan EL, Imai Y, Müller R, Flannick J, Bonewald L, Burtt N. The musculoskeletal knowledge portal: making omics data useful to the broader scientific community. J Bone Miner Res. September 2020;35(9):1626-1633.