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A Novel GALNT3 Mutation in a Pseudoautosomal Dominant Form of Tumoral Calcinosis: Evidence That the Disorder Is Autosomal Recessive

Departments of Medicine (S.I., M.J.E.) and Medical and Molecular Genetics (M.J.E.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and Department of Medicine (K.W.L.), Duke University Medical Center and Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Michael J. Econs, M.D., Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, Indiana 46202-5121. E-mail: mecons{at}iupui.edu.

Abstract

Familial tumoral calcinosis is a rare metabolic disorder, characterized by ectopic calcification and hyperphosphatemia. Recently biallelic mutations in the GalNAc transferase 3 (GALNT3) gene were identified in two families with tumoral calcinosis. In the present study, we performed mutation analysis of the GALNT3 gene in a multigenerational family, which was originally described to have an autosomal dominant form of tumoral calcinosis. We identified a novel splice site mutation in intron 1 (IVS1–2at), likely leading to skipping of exon 2. The proband was a compound heterozygote for the splice site mutation and the previously reported nonsense mutation (484CT; R162X). His affected maternal great uncle was homozygous for the splice site mutation. Biallelic mutations found in two generations demonstrated that the family had pseudoautosomal dominant inheritance, confirming that tumoral calcinosis is in fact an autosomal recessive trait. However, genetic and biochemical findings suggest that carriers of a single mutation may also manifest subtle biochemical abnormalities. Furthermore, coexpression of GALNT3 and fibroblast growth factor 23 (FGF23), a key regulator of phosphate homeostasis, in certain tissues suggests that O-glycosylation of FGF23 by GALNT3 may be necessary for proper function of FGF23.

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