title: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis.
abstract: Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-alpha-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.
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5121, USA.
authors: Shoji
authors: S
authors: Ichikawa
authors: Erik A
authors: EA
authors: Imel
authors: Mary L
authors: ML
authors: Kreiter
authors: Xijie
authors: X
authors: Yu
authors: Donald S
authors: DS
authors: Mackenzie
authors: Andrea H
authors: AH
authors: Sorenson
authors: Regina
authors: R
authors: Goetz
authors: Moosa
authors: M
authors: Mohammadi
authors: Kenneth E
authors: KE
authors: White
authors: Michael J
authors: MJ
authors: Econs
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D000090265:Klotho Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D040681:Structural Homology, Protein
chemical_list: C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
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