Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia.

IF 3 Q2 ENDOCRINOLOGY & METABOLISM Journal of the Endocrine Society Pub Date : 2024-10-22 eCollection Date: 2024-10-29 DOI:10.1210/jendso/bvae184
Hajime Kato, Yasuki Ishihara, Yasuhisa Ohata, Koki Irie, So Watanabe, Soichiro Kimura, Yoshitomo Hoshino, Naoko Hidaka, Yuka Kinoshita, Yuki Taniguchi, Hiroshi Kobayashi, Demetrios T Braddock, Takuo Kubota, Keiichi Ozono, Masaomi Nangaku, Noriko Makita, Nobuaki Ito
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Abstract

Context: Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated.

Objective: This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH.

Methods: Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PPi)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification.

Results: We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PPi, 14 patients (45%) showed decreased plasma PPi concentrations; however, PPi concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification.

Conclusion: Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PPi on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.

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突变类型对 X-连锁低磷血症成年患者异位骨化的影响
背景:X-连锁低磷血症(XLH)异位骨化的致病因素仍有待阐明:本研究旨在探讨磷酸调节内肽酶同源物、X-连锁基因(PHEX)与XLH异位骨化之间的基因型-表型相关性:方法:对生化数据、脊柱计算机断层扫描和髋关节/膝关节的 X 光片进行了回顾性审查。进行了基因分析和血浆无机焦磷酸(PPi)的测定,PPi是一种有效的组织钙化抑制剂。利用无义介导衰变(NMD)和三维结构建模预测了PHEX突变对蛋白质功能的影响。前/后纵韧带和黄韧带骨化指数(OA/OP/OY指数)和OA/OP/OY指数之和(OS指数)被用来量化脊柱韧带骨化的严重程度。髋关节/膝关节骨关节炎的严重程度采用凯尔格伦-劳伦斯分类法进行评估:我们对来自 27 个非血缘关系、非近亲家庭的 33 名患者中的 28 名患者的 24 个不同致病 PHEX 变体进行了检测。在对血浆样本进行PPi分析的31名患者中,有14名患者(45%)的血浆PPi浓度下降;但PPi浓度与突变类型或异位骨化无关。NMD不敏感突变女性患者的成纤维细胞生长因子23水平呈低于NMD敏感突变男性患者的趋势,但未达到统计学意义。两种模型均未发现PHEX致病变异与异位骨化之间的相关性:结论:两种模型均未发现PHEX致病变体与异位骨化之间的相关性。PPi对XLH成人异位骨化的影响揭示了一些趋势,应通过大样本量进行研究。
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来源期刊
Journal of the Endocrine Society
Journal of the Endocrine Society Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
5.50
自引率
0.00%
发文量
2039
审稿时长
9 weeks
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