A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis
A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis
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DOI：
10.1172/jci31330
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Econs, Michael J.
中科院分区：
文献类型：
--
作者：
Ichikawa, Shoji;Lmel, Erik A.;Econs, Michael J.
家族性肿瘤性钙质沉着症的特征在于由于FGF 23或UDP-N-乙酰基-α-D-半乳糖胺：多肽N-乙酰基半乳糖胺转移酶3（GALNT 3）的失活突变引起的异位钙化和高磷酸盐血症。在此，我们报告了一个13岁女孩的KLOTHO（KL）基因的纯合错义突变（H193 R），她患有严重的肿瘤性钙质沉着症，伴有硬脑膜和颈动脉钙化。该患者表现出矿物质离子稳态缺陷，伴有显著的高磷酸盐血症和高钙血症以及甲状旁腺激素和FGF 23血清水平升高。映射到黑芥子酶，KL的植物同源物的晶体结构上的H193 R突变，揭示了该组氨酸残基是在深催化裂缝的基础上，该组氨酸突变为精氨酸应该使KL的推定糖苷酶结构域（KL 1）不稳定，从而减弱膜结合和分泌KL的产生。事实上，与野生型KL相比，H193 R KL的表达和分泌在体外显著降低，导致FGF 23通过其同源FGF受体发出信号的能力降低。总之，我们的研究结果提供了我们认为是人类KL功能缺失突变损害FGF 23生物活性的第一个证据，强调了KL在人类FGF 23介导的磷酸盐和维生素D稳态中的重要作用。
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.