GALNT3 – Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

GALNT3 encodes the glycosyltransferase ppGalNAc-T3, which O-glycosylates the phosphaturic hormone FGF23. Biallelic inactivating variants in GALNT3 cause autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC) and its skeletal variant, hyperphosphatemic hyperostosis syndrome (HHS), by impairing FGF23 glycosylation, reducing intact hormone secretion, and leading to phosphate retention and ectopic calcifications ([PMID:15599692]; [PMID:17311862]).

Over 54 unrelated probands have been reported with homozygous or compound heterozygous GALNT3 variants, including nonsense, frameshift, splice-site, and missense mutations. A recurrent founder splice mutation c.1524+1G>A has been seen in Middle Eastern families, and novel missense changes such as c.767G>T (p.Gly256Val) were described in a consanguineous Caucasian pedigree demonstrating phenotypic variability ([PMID:25249269]; [PMID:19297793]). In a four-generation Iranian family, a homozygous c.782G>A (p.Arg261Gln) variant co-segregated with disease among affected relatives, confirming autosomal recessive inheritance and full penetrance in homozygotes ([PMID:32125652]).

Segregation analyses in multiple consanguineous kindreds have identified at least 4 additional affected relatives with homozygous or compound heterozygous GALNT3 variants, underscoring robust co-segregation with HFTC/HHS. Phenotypic spectrum ranges from painful periarticular calcifications and hyperostotic bone pain to episodic diaphysitis and myalgia ([PMID:19297793]; [PMID:25249269]).

Functional assessment in patient cells and animal models demonstrates that loss of ppGalNAc-T3 activity leads to incomplete O-glycosylation of FGF23, enhanced proteolytic cleavage, markedly reduced circulating intact FGF23, and accumulation of inactive C-terminal fragments. GALNT3-null mice recapitulate hyperphosphatemia, low intact Fgf23, elevated C-terminal fragments, and hyperostotic bone changes, confirming a loss-of-function mechanism ([PMID:17311862]; [PMID:19213845]).

Mechanistically, GALNT3 deficiency causes FGF23 misprocessing, resulting in renal phosphate retention (elevated TmP/GFR) and elevated 1,25(OH)2D. Histopathology of calcified masses shows calcium-phosphate deposition surrounded by macrophages and osteoclast-like giant cells, consistent with HFTC pathology. Dental studies reveal high-penetrance root and pulp defects in NIH cohorts, linking hyperphosphatemia to tooth anomalies ([PMID:33977199]).

In summary, definitive evidence establishes GALNT3 as a critical gene in phosphate homeostasis disorders. Genetic testing for GALNT3 variants is essential for accurate diagnosis and differentiation from osteomyelitis or bone neoplasia. Therapeutically, interventions that restore FGF23 glycosylation or mimic its activity may correct hyperphosphatemia and prevent calcific sequelae.

Key Take-home: Autosomal recessive GALNT3 loss-of-function variants cause HFTC/HHS by impairing FGF23 O-glycosylation, leading to hyperphosphatemia, ectopic calcifications, and hyperostosis with high diagnostic and therapeutic utility.

References

• Journal of molecular medicine (Berlin, Germany) • 2005 • Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. PMID:15599692
• The Journal of clinical endocrinology and metabolism • 2007 • Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. PMID:17311862
• BMC Genetics • 2014 • Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. PMID:25249269
• The Turkish journal of pediatrics • 2019 • Recessive mutation in GALNT3 causes hyperphosphatemic familial tumoral calcinosis associated with chronic recurrent multifocal osteomyelitis. PMID:31559735
• Endocrinology • 2014 • Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse. PMID:25051439
• JBMR Plus • 2021 • A Cross-Sectional Cohort Study of the Effects of FGF23 Deficiency and Hyperphosphatemia on Dental Structures in Hyperphosphatemic Familial Tumoral Calcinosis. PMID:33977199
• Endocrinology • 2009 • Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. PMID:19213845

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