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Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism
Journal of bone and mineral research, 2023-05, Vol.38 (5), p.678-691
Hassan, Neelam
Gregson, Celia L.
Tang, Haotian
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.
2023
Details
Autor(en) / Beteiligte
Hassan, Neelam
Gregson, Celia L.
Tang, Haotian
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.
Titel
Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism
Ist Teil von
Journal of bone and mineral research, 2023-05, Vol.38 (5), p.678-691
Ort / Verlag
Hoboken, USA: John Wiley & Sons, Inc
Erscheinungsjahr
2023
Link zum Volltext
Quelle
Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
Beschreibungen/Notizen
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.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. © 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).
Sprache
Englisch
Identifikatoren
ISSN: 0884-0431
eISSN: 1523-4681
DOI: 10.1002/jbmr.4795
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10729283
Format
–
Schlagworte
Bone Density - genetics
,
Bone mass
,
Bone mineral density
,
Calcinosis
,
EXOME SEQUENCING
,
Femur
,
Fibroblast growth factor 23
,
Fibroblast growth factor receptor 1
,
GALNT3
,
Genome-Wide Association Study
,
Genomes
,
HIGH BONE MASS
,
Humans
,
Hyperphosphatemia
,
Klotho protein
,
Lumbar Vertebrae - physiology
,
Manganese
,
Metabolism
,
MONOGENIC
,
Osteoporosis
,
Osteoporosis - genetics
,
PHOSPHATE
,
Phosphates
,
Quantitative trait loci
,
Spine (lumbar)
,
Therapeutic targets
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