GALNT3 – familial tumoral calcinosis

Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by hyperphosphatemia, elevated renal phosphate reabsorption, and periarticular ectopic calcifications. Inactivating biallelic mutations in UDP-N-acetyl-α-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) result in loss of O-glycosylation of fibroblast growth factor 23 (FGF23), leading to inadequate secretion of intact FGF23 and consequent phosphate retention (PMID:15133511). FTC typically presents in childhood or adolescence with large tumoral masses, hyperphosphatemia (HP:0002905), and normal renal function.

Genetic evidence demonstrates autosomal recessive inheritance, with numerous unrelated families harboring biallelic GALNT3 null or missense variants. Initial linkage and sequencing studies identified deleterious frameshift and nonsense mutations in multiple kindreds (e.g., c.86dup (p.Phe30fs), c.803dup (p.Thr269fs), c.484C>T (p.Arg162Ter)) segregating with disease across consanguineous pedigrees (PMID:15133511; PMID:15687324). Case reports have since expanded the variant spectrum to include splice-site (c.516-2A>G), missense (c.1076C>A (p.Thr359Lys)) and founder alleles, identified in over 20 affected individuals worldwide (PMID:16868048; PMID:16940445).

Segregation analysis in large families, including a 40-year follow-up of a kindred with seven affected siblings among 16 children, confirmed co-segregation of GALNT3 truncating mutations with FTC phenotype (PMID:19255228). Additional multigenerational families showed compound heterozygosity for splice-site and nonsense mutations, reaffirming autosomal recessive transmission despite pseudo-dominant pedigrees (PMID:15687324).

Functional studies support a haploinsufficiency mechanism. In vitro assays of mutant GALNT3 demonstrate reduced O-glycosylation of FGF23, leading to enhanced proteolytic cleavage and low intact FGF23 despite elevated C-terminal fragments (PMID:16940445; PMID:17311862). Galnt3 knockout mice exhibit hyperphosphatemia, decreased circulating intact Fgf23, and elevated Fgf23 expression in bone, recapitulating the human biochemical phenotype (PMID:19213845). Cell models derived from affected patients show increased mineral nodule formation, further linking loss of GALNT3 function to phosphate dysregulation (PMID:25899975).

No substantial conflicting evidence has been reported; all reported GALNT3 variants in FTC have consistent loss-of-function effects. While heterozygous carriers may exhibit subtle biochemical abnormalities, only biallelic mutations cause overt FTC.

Integration of genetic and functional data establishes a definitive gene-disease relationship between GALNT3 and familial tumoral calcinosis. Molecular testing for GALNT3 mutations enables definitive diagnosis, informs family counseling, and guides targeted phosphate-lowering therapies. Key take-home: GALNT3 loss-of-function mutations cause FTC via impaired FGF23 glycosylation, making genetic screening essential for early diagnosis and management.

References

• Nature Genetics • 2004 • Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. PMID:15133511
• Journal of Clinical Endocrinology and Metabolism • 2005 • A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. PMID:15687324
• Journal of Bone and Joint Surgery American Volume • 2009 • Familial tumoral calcinosis: a forty-year follow-up on one family. PMID:19255228
• Journal of Clinical Endocrinology and Metabolism • 2006 • Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. PMID:16940445
• Calcified Tissue International • 2015 • Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization. PMID:25899975
• 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

Evidence Based Scoring (AI generated)