Two novel rare variants in the PTH gene found in patients with hypoparathyroidism

IF 2.5 Q3 ENDOCRINOLOGY & METABOLISM
Yue Jiang , An Song , Jiajia Wang , Xinqi Cheng , Jing Yang , Yan Jiang , Mei Li , Weibo Xia , Xiaoping Xing , Min Nie , Ou Wang
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Abstract

Objectives

Hypoparathyroidism (HP) is a rare endocrine disorder caused by parathyroid hormone (PTH) deficiency. The PTH is a candidate gene for familial isolated hypoparathyroidism (FIH). This study aimed to investigate the pathogenicity of two novel rare variants (RVs) of PTH through in vitro functional study.

Methods

Targeted next-generation sequencing was used to identify candidate gene mutations. Clinical data were retrospectively collected. Wild-type (WT) PTH was used as a template for site-directed mutagenesis to create mutant eukaryotic expression plasmids, which were transfected into cells. Treated with or without 4-phenylbutyric acid (4-PBA), the levels of intact PTH (iPTH) and PTH (1-84) were measured by chemiluminescence, and protein expression was assessed using Western blotting.

Results

Two patients carrying PTH mutations (c.154G > A: p.Val52Ile, c.270G > T: p.Leu90Phe) were identified. Patient 1, a 45-year-old male, presented with carpal and pedal numbness, muscle cramps, and low serum calcium (1.29 mmol/L). Patient 2, a 12-year-old female, had muscle twitches, convulsions, low calcium (1.50 mmol/L), and iPTH of 4 pg/mL. The iPTH or PTH (1-84) levels in the medium transfected with mutant Val52Ile and Leu90Phe PTH decreased by 31%–38%, and 51%–96% compared to WT (allP < 0.05), which were not rescued by 4-PBA. No significant changes in intracellular PTH expression were observed.

Conclusions

In this study, two novel RVs of PTH (Val52Ile and Leu90Phe) were identified that may impair hormone synthesis and secretion. Our study has broadened the mutation spectrum of the PTH and shed light on potential mechanisms underlying FIH.
在甲状旁腺功能减退症患者中发现了两种新的罕见的PTH基因变异
目的甲状旁腺功能减退症(HP)是一种罕见的由甲状旁腺激素(PTH)缺乏引起的内分泌疾病。PTH是家族性分离性甲状旁腺功能减退症(FIH)的候选基因。本研究旨在通过体外功能研究两种新型PTH罕见变异(RVs)的致病性。方法采用靶向新一代测序技术鉴定候选基因突变。回顾性收集临床资料。利用野生型(WT) PTH作为定点诱变模板,构建真核表达质粒突变体,并将其转染到细胞中。4-苯基丁酸(4-PBA)处理或不处理后,化学发光法测定完整PTH (iPTH)和PTH(1-84)水平,Western blotting法测定蛋白表达。结果2例患者携带PTH突变(c.154G >;A: p.Val52Ile, c.270G >;T: p.Leu90Phe)。患者1,45岁男性,表现为腕和足部麻木,肌肉痉挛,低血钙(1.29 mmol/L)。患者2,12岁女性,肌肉抽搐,抽搐,低钙(1.50 mmol/L), iPTH为4 pg/mL。转染突变体Val52Ile和Leu90Phe的培养基中iPTH或PTH(1-84)水平与WT相比分别下降31% ~ 38%和51% ~ 96% (allP <;0.05),未被4-PBA抢救。细胞内PTH表达无明显变化。结论本研究发现两种新的PTH RVs (Val52Ile和Leu90Phe)可能影响激素的合成和分泌。我们的研究拓宽了PTH的突变谱,揭示了FIH的潜在机制。
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来源期刊
Osteoporosis and Sarcopenia
Osteoporosis and Sarcopenia Orthopedics, Sports Medicine and Rehabilitation, Endocrinology, Diabetes and Metabolism, Obstetrics, Gynecology and Women's Health, Geriatrics and Gerontology
自引率
5.00%
发文量
23
审稿时长
66 days
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