TRPV4基因变异引起先天性骨病遗传学分析

doi:10.12372/jcp.2023.22e1509

临床儿科杂志 ›› 2023, Vol. 41 ›› Issue (7): 530-536.doi: 10.12372/jcp.2023.22e1509

TRPV4基因变异引起先天性骨病遗传学分析

张文妍¹, 姚子明², 张学军², 张耀东³, 王凌飞⁴, 胡旭昀¹^,³, 郝婵娟¹^,³()

1.国家儿童医学中心首都医科大学附属北京儿童医院北京市儿科研究所出生缺陷遗传学研究北京市重点实验室儿科重大疾病研究教育部重点实验室（北京 100045）
2.国家儿童医学中心首都医科大学附属北京儿童医院骨科（北京 100045）
3.郑州大学附属儿童医院河南省儿童医院郑州儿童医院儿科研究所河南省儿童遗传代谢疾病重点实验室（河南郑州 450053）
4.郑州大学附属儿童医院河南省儿童医院郑州儿童医院内分泌科（河南郑州 450053）

收稿日期:2022-11-15 出版日期:2023-07-15 发布日期:2023-07-05
通讯作者: 郝婵娟 E-mail:hchjhchj@163.com
基金资助:
国家自然科学基金项目(32270728)

Genetic characteristics of TRPV4-related congenital skeletal disorder

ZHANG Wenyan¹, YAO Ziming², ZHANG Xuejun², ZHANG Yaodong³, WANG Lingfei⁴, HU Xuyun¹^,³, HAO Chanjuan¹^,³()

1. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
2. Department of Orthopedics, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
3. Henan Key Laboratory of Inherited Metabolic Diseases, Pediatric Research Institute of Zhengzhou Children’s Hospital, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou 450053, Henan, China
4. Department of Endocrinology, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou 450053, Henan, China

Received:2022-11-15 Online:2023-07-15 Published:2023-07-05
Contact: HAO Chanjuan E-mail:hchjhchj@163.com

摘要/Abstract

摘要：

目的对4例不同严重程度的先天性骨病患儿进行基因诊断以明确其遗传学病因。总结临床特点并进行基因型-表型分析。方法收集4例患儿的临床资料，采集患儿及父母外周血并提取DNA，患儿行全外显子组测序，根据ACMG遗传变异分类标准与指南判断变异位点致病性，对患儿及父母进行Sanger测序验证。结果 4例患儿均携带TRPV4基因杂合变异，其中2个错义变异遗传自患病父母，1个缺失插入变异和1个错义变异为新生变异，分别为c.2077G>A (p.Val693Met)，c.1199G>A (p.Arg400Gln)，c.1657delinsACTA (p.Tyr553delinsThrAsn)，和c.259G>A (p.Glu87Lys)，以上位点国内外未见报道。1-3号患儿有不同程度的身材矮小，4例患儿均有先天性脊柱侧弯及其他骨骼系统异常。分别诊断为轻型变形性骨发育不良、3型常染色体显性短躯干、变形性骨发育不良合并类扭伤型侏儒及经典型变形性骨发育不良。携带相同变异的患儿父亲/母亲有轻度的骨骼畸形。结论 TRPV4基因不同位点变异引起的先天性骨病表型互有重叠但严重程度差异较大，可根据分子诊断结果进行鉴别诊断及临床干预。

关键词: TRPV4基因, 先天性骨病, 基因型-表型, 分子诊断

Abstract:

Objective To identify the genetic causes of four patients with different severity of congenital skeletal disorder by genetic diagnosis, and to summarize the clinical characteristics and analyze the genotype-phenotype. Methods The clinical data of four patients were collected. The peripheral blood of the patients and their parents were collected and DNA was extracted. Whole exome sequencing of patients was performed and variants were classified following the interpretation standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. Putative pathogenic variants were verified by Sanger sequencing. Results The four patients all carried TRPV4 heterozygous variants. Two missense variants were inherited from affected parents, and one deletion insertion variant and missense variant were de novo: c.2077G>A (p.Val693Met), c.1199G>A (p.Arg400Gln), c.1657delinsACTA (p.Tyr553delinsThrAsn) and c.259G>A (p.Glu87Lys). None of these variants have been previously reported. Patients 1-3 had varying degrees of short stature, and all 4 had congenital scoliosis and other skeletal deformities. They were diagnosed as mild Metatropic Dysplasia, Autosomal Dominant Brachyomia type 3, Parastremmatic Dysplasia with Metatropic Dysplasia, and classic Metatropic Dysplasia respectively. Their parents with the same variant also had mild bone deformity. Conclusions The phenotypes of congenital skeletal disorders caused by different variants in TRPV4 gene were widely heterogeneous. Patients often present with overlapping skeletal system abnormalities. Therefore, differential diagnosis and clinical intervention can be conducted according to the molecular diagnosis results.

Key words: TRPV4 gene, congenital skeletal disorder, genotype-phenotype, molecular diagnosis

张文妍, 姚子明, 张学军, 张耀东, 王凌飞, 胡旭昀, 郝婵娟. TRPV4基因变异引起先天性骨病遗传学分析[J]. 临床儿科杂志, 2023, 41(7): 530-536.

ZHANG Wenyan, YAO Ziming, ZHANG Xuejun, ZHANG Yaodong, WANG Lingfei, HU Xuyun, HAO Chanjuan. Genetic characteristics of TRPV4-related congenital skeletal disorder[J]. Journal of Clinical Pediatrics, 2023, 41(7): 530-536.

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参考文献 34

[1]	Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision[J]. Am J Med Genet A, 2019, 179(12): 2393-2419. doi: 10.1002/ajmg.a.61366 pmid: 31633310
[2]	Ürel-Demir G, Şimşek-Kiper PÖ, Öncel İ, et al. Natural history of TRPV4-related disorders: from skeletal dysplasia to neuromuscular phenotype[J]. Eur J Paediatr Neurol, 2021, 32: 46-55. doi: 10.1016/j.ejpn.2021.03.011
[3]	Nishimura G, Lausch E, Savarirayan R, et al. TRPV4-associated skeletal dysplasias[J]. Am J Med Genet C Semin Med Genet, 2012, 160C(3): 190-204. doi: 10.1002/ajmg.c.v160c.3
[4]	Geneviève D, Le Merrer M, Feingold J, et al. Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature[J]. Am J Med Genet A, 2008, 146A(8): 992-996. doi: 10.1002/ajmg.a.32191 pmid: 18348257
[5]	Krakow D, Vriens J, Camacho N, et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia[J]. Am J Hum Genet, 2009, 84(3): 307-315. doi: 10.1016/j.ajhg.2009.01.021 pmid: 19232556
[6]	Rock MJ, Prenen J, Funari VA, et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia[J]. Nat Genet, 2008, 40(8): 999-1003. doi: 10.1038/ng.166
[7]	Nishimura G, Dai J, Lausch E, et al. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations[J]. Am J Med Genet A, 2010, 152A(6): 1443-1449. doi: 10.1002/ajmg.a.33414 pmid: 20503319
[8]	Lamandé SR, Yuan Y, Gresshoff IL, et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet[J]. Nat Genet, 2011, 43(11): 1142-1146. doi: 10.1038/ng.945
[9]	White JP, Cibelli M, Urban L, et al. TRPV4: molecular conductor of a diverse orchestra[J]. Physiol Rev, 2016, 96(3): 911-973. doi: 10.1152/physrev.00016.2015 pmid: 27252279
[10]	Everaerts W, Nilius B, Owsianik G. The vanilloid transient receptor potential channel TRPV4: from structure to disease[J]. Prog Biophys Mol Biol, 2010, 103(1): 2-17. doi: 10.1016/j.pbiomolbio.2009.10.002
[11]	Arniges M, Fernández-Fernández JM, Albrecht N, et al. Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking[J]. J Biol Chem, 2006, 281(3): 1580-1586. doi: 10.1074/jbc.M511456200 pmid: 16293632
[12]	Deng Z, Paknejad N, Maksaev G, et al. Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms[J]. Nat Struct Mol Biol, 2018, 25(3): 252-260. doi: 10.1038/s41594-018-0037-5 pmid: 29483651
[13]	Loukin SH, Teng J, Kung C. A channelopathy mechanism revealed by direct calmodulin activation of TrpV4[J]. Proc Natl Acad Sci U S A, 2015, 112(30): 9400-9405. doi: 10.1073/pnas.1510602112
[14]	Strotmann R, Schultz G, Plant TD. Ca²⁺-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site[J]. J Biol Chem, 2003, 278(29): 26541-26549. doi: 10.1074/jbc.M302590200 pmid: 12724311
[15]	Ji C, McCulloch CA. TRPV4 integrates matrix mecha-nosensing with Ca²⁺ signaling to regulate extracellular matrix remodeling[J]. FEBS J, 2021, 288(20): 5867-5887. doi: 10.1111/febs.v288.20
[16]	Toft-Bertelsen TL, MacAulay N. TRPing to the point of clarity: understanding the function of the complex TRPV4 ion channel[J]. Cells, 2021, 10(1): 165. doi: 10.3390/cells10010165
[17]	Camacho N, Krakow D, Johnykutty S, et al. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia[J]. Am J Med Genet A, 2010, 152A(5): 1169-1177. doi: 10.1002/ajmg.a.v152a:5
[18]	Dicks AR, Maksaev GI, Harissa Z, et al. Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes[J]. Elife, 2023, 12: e71154. doi: 10.7554/eLife.71154
[19]	Hou W, Fu H, Liu X, et al. Cation channel transient receptor potential vanilloid 4 mediates topography-induced osteoblastic differentiation of bone marrow stem cells[J]. ACS Biomater Sci Eng, 2019, 5(12): 6520-6529. doi: 10.1021/acsbiomaterials.9b01237
[20]	Clark AL, Votta BJ, Kumar S, et al. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice[J]. Arthritis Rheum, 2010, 62(10): 2973-2983. doi: 10.1002/art.v62:10
[21]	Willard VP, Leddy HA, Palmer D, et al. Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis[J]. Stem Cells, 2021, 39(11): 1447-1456. doi: 10.1002/stem.3440 pmid: 34427363
[22]	Rorden C, Griswold MC, Moses N, et al. Radiographical survey of osteochondrodysplasia in Scottish Fold cats caused by the TRPV4 gene variant[J]. Hum Genet, 2021, 140(11): 1525-1534. doi: 10.1007/s00439-021-02337-5 pmid: 34406467
[23]	Ji C, Mcculloch CA. TRPV4 integrates matrix mechanosensing with Ca²⁺ signaling to regulate extracellular matrix remodeling[J]. FEBS J, 2021, 288(20): 5867-5887. doi: 10.1111/febs.v288.20
[24]	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. doi: 10.1038/gim.2015.30 pmid: 25741868
[25]	Nishimura G, Kizu R, Kijima Y, et al. Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects[J]. Am J Med Genet A, 2003, 120A(4): 498-502. pmid: 12884428
[26]	Nemec SF, Cohn DH, Krakow D, et al. The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family)[J]. Pediatr Radiol, 2012, 42(1): 15-23. doi: 10.1007/s00247-011-2229-6
[27]	Kozlowski K. La dysostose spondylometaphysaire[M]. Presse Méd., 1967, 75: 2769-2774.
[28]	Poznanski AK. Progress in pediatric radiology[M]. Vol. 4: Intrinsic Diseases of Bones:The Radiological Society of North America, 1973.
[29]	Kannu P, Aftimos S, Mayne V, et al. Metatropic dysplasia: clinical and radiographic findings in 11 patients demonstrating long-term natural history[J]. Am J Med Genet A, 2007, 143A(21): 2512-2522. pmid: 17879966
[30]	Geneviève D, Le Merrer M, Munnich A, et al. Long-term follow-up in a patient with metatropic dysplasia[J]. Am J Med Genet A, 2005, 135(3): 342-343. pmid: 15889420
[31]	Vriens J, Owsianik G, Janssens A, et al. Determinants of 4 alpha-phorbol sensitivity in transmembrane domains 3 and 4 of the cation channel TRPV4[J]. J Biol Chem, 2007, 282(17): 12796-12803. doi: 10.1074/jbc.M610485200 pmid: 17341586
[32]	Klausen TK, Pagani A, Minassi A, et al. Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study[J]. J Med Chem, 2009, 52(9): 2933-2939. doi: 10.1021/jm9001007 pmid: 19361196
[33]	McCray BA, Schindler A, Hoover-Fong JE, et al. Autosomal dominant TRPV4 disorders[DB/OL]. GeneReviews® [Internet]: University of Washington, Seattle, 2020.
[34]	袁佳雨, 孙东兰, 李亚洲. TRPV4基因的两个不同变异导致变形性骨发育不良表型严重程度差异[J]. 中国组织化学与细胞化学杂志, 2021, 30(6): 545-551.

序号	性别	年龄/岁	身高/cm	脊柱异常	胸廓畸形	关节异常	四肢异常	其他	家族史
1	男	10	115	先天性脊柱后侧突，T1-T7广泛椎体畸形，扁平椎	胸廓塌陷	膝关节炎	左足多趾	后背肌肉纤维变性	母身高155 cm，有膝关节炎病史
2	女	11	140	先天性脊柱后侧突，斜颈，多发椎体形态不规则伴融合，脊髓纵裂	右肋11条，第3~5肋融合，左肋12条，5~6及7~10肋融合	无	无	无	父冬季关节弹响，爷爷有膝关节炎
3	男	3	98	先天性脊柱后突，广泛、严重的扁平椎	无	腕、膝、踝关节活动受限，膝外翻，因膝关节炎疼痛，无法自主步行	双侧尺、桡骨骨干弯曲，髋臼异常，股骨呈哑铃状	无	无
4	男	1	85	先天性脊柱侧弯	无	暂无	左侧股骨呈哑铃状，较右侧短	无	无

序号	变异名称	氨基酸改变	保守性	软件预测	外显子位置	合子性	父亲携带情况	母亲携带情况	致病性分级
1	c.2077G>A	p.Val693Met	高度保守	有害变异	15	杂合	不携带	杂合	致病变异
2	c.1199G>A	p.Arg400Gln	高度保守	有害变异	6	杂合	杂合	不携带	致病变异
3	c.1657delinsACTA	p.Tyr553delinsThrAsn	高度保守	--	12	杂合	不携带	不携带	致病变异
4	c.259G>A	p.Glu87Lys	高度保守	有害变异	1	杂合	不携带	不携带	致病变异

TRPV4基因变异引起先天性骨病遗传学分析

Genetic characteristics of TRPV4-related congenital skeletal disorder

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