NDLI: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis

Content Provider	PubMed Central
Author	Ichikawa, Shoji Imel, Erik A. Kreiter, Mary L. Yu, Xijie Mackenzie, Donald S. Sorenson, Andrea H. Goetz, Regina Moosa, Md. I White, Kenneth E. Econs, Michael J.
Copyright Year	2007
Abstract	Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO (KL) gene of a 13-year-old girl who presented with severe tumoral calcinosis with dural and carotid artery calcifications. This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia and hypercalcemia as well as elevated serum levels of parathyroid hormone and FGF23. Mapping of H193R mutation onto the crystal structure of myrosinase, a plant homolog of KL, revealed that this histidine residue was at the base of the deep catalytic cleft and mutation of this histidine to arginine should destabilize the putative glycosidase domain (KL1) of KL, thereby attenuating production of membrane-bound and secreted KL. Indeed, compared with wild-type KL, expression and secretion of H193R KL were markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Taken together, our findings provide what we believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans.
Related Links	http://dx.doi.org/10.1172/jci31330
Ending Page	2691
Page Count	8
Starting Page	2684
File Format	PDF
ISSN	00219738
Journal	The Journal of Clinical Investigation
Issue Number	9
Volume Number	117
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2007-09-04
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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