Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene.

Abstract

CONTEXT:

Familial tumoral calcinosis (TC) is a rare autosomal recessive disorder characterized by metastatic calcifications, often periarticular. Biochemical findings include hyperphosphatemia, high 1,25-dihydroxyvitamin D levels, and elevated tubular maximum for phosphate reabsorption per deciliter of glomerular filtrate (TmP/GFR). TC is caused by biallelic mutations of the genes encoding either fibroblast growth factor 23 (FGF23) or uridine diphosphate-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc transferase 3 or GALNT3).

OBJECTIVE:

The objective was to identify mutations in FGF23 or GALNT3 responsible for a mild TC phenotype by DNA sequencing and to determine serum FGF23 levels by ELISA.

PATIENTS OR OTHER PARTICIPANTS:

The subject was a 25-yr-old Caucasian woman with eyelid calcifications and biochemical features of TC.

RESULTS:

Eyelid biopsy revealed superficial dermis calcifications. There was no history of metastatic calcifications, mineral homeostasis abnormalities, or renal dysfunction. Biochemistry revealed normal levels of calcium, creatinine, PTH, and 25-hydroxyvitamin D, with elevated phosphorous, TmP/GFR, and high normal 1,25-dihydroxyvitamin D levels. Intact FGF23 was undetectable (< 3 pg/ml), whereas C-terminal FGF23 was elevated (698.2 RU/ml). Mutation detection revealed compound heterozygosity for two novel mutations in the glycosyl transferase domain of the GALNT3 gene.

CONCLUSION:

Previously reported GALNT3 mutations in TC have been null mutations. This study shows that missense mutations affecting the glycosyl transferase domain of GalNAc transferase 3 also cause TC. Elevated C-terminal FGF23 fragments with undetectable intact FGF23 suggest that the mutant enzyme lacks the ability to glycosylate FGF23 and that glycosylation by GalNAc transferase 3 is necessary for secretion of functional full-length FGF23.

• Authors: Shoji Ichikawa, Erik A Imel, Andrea H Sorenson, Rebecca Severe, Paul Knudson, Gerald J Harris, Joseph L Shaker, Michael J Econs
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 91 Issue 11 Pg. 4472-5 (Nov 2006) ISSN: 0021-972X [Print] United States
• PMID: 16940445 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• FGF23 protein, human
• Neoplasm Proteins
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• Glycosyltransferases
• N-Acetylgalactosaminyltransferases

Topics

• Adult
• Calcinosis (genetics)
• DNA Mutational Analysis
• Eyelids (pathology)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood)
• Glycosyltransferases (genetics)
• Humans
• Mutation, Missense
• N-Acetylgalactosaminyltransferases (genetics)
• Neoplasm Proteins (genetics)
• Protein Structure, Tertiary (genetics)
• Skin Diseases (genetics)
• Polypeptide N-acetylgalactosaminyltransferase