Hyperphosphatemic familial tumoral calcinosis caused by a novel variant in the GALNT3 gene

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 lociThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism

Hassan

Gregson

Tang

et al. 2020

Journal of Bone and Mineral Research

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Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review

Cherian,

Vinodhini

et al. 2024

Calcif Tissue Int

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Non-neoplastic bone, joint, and soft tissue pathology: What every pathologist should know

Klein

2024

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Hyperphosphatemic familial tumoral calcinosis caused by a novel variant in the GALNT3 gene

Cited by 8 publications

References 19 publications

Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism

Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism

Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review

Non-neoplastic bone, joint, and soft tissue pathology: What every pathologist should know

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