Faculty Collaboration Database

Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J Clin Endocrinol Metab 2006 Nov;91(11):4472-5

Date

08/31/2006

Pubmed ID

16940445

DOI

10.1210/jc.2006-1247

Scopus ID

2-s2.0-33751533213 (requires institutional sign-in at Scopus site)   72 Citations

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.

Author List

Ichikawa S, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, Shaker JL, Econs MJ

Authors

Gerald J. Harris MD Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Paul Knudson MD Associate Professor in the Medicine department at Medical College of Wisconsin
Joseph L. Shaker MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Calcinosis
DNA Mutational Analysis
Eyelids
Female
Fibroblast Growth Factors
Glycosyltransferases
Humans
Mutation, Missense
N-Acetylgalactosaminyltransferases
Neoplasm Proteins
Protein Structure, Tertiary
Skin Diseases