国际口腔医学杂志

国际口腔医学杂志 ›› 2026, Vol. 53 ›› Issue (4): 562-569.doi: 10.7518/gjkq.2026624

• 综述 • 上一篇    

ARHGAP29基因在非综合征型唇腭裂中作用机制的研究进展

佘梦(),马坚()   

  1. 宁夏医科大学口腔医学院 宁夏口腔疾病研究重点实验室 宁夏医科大学总医院口腔医院 银川 750004
  • 收稿日期:2025-03-01 修回日期:2026-04-24 出版日期:2026-07-01 发布日期:2026-06-25
  • 通讯作者: 马坚
  • 作者简介:佘梦，硕士，Email：15121979678@163.com
  • 基金资助:
    宁夏回族自治区重点研发计划(2022BEG03159)

Research progress on the mechanism of ARHGAP29 in non-syndromic cleft lip with or without cleft palate

Meng She(),Jian Ma()   

  1. College of Stomatology, Ningxia Medical University, Ningxia Key Laboratory of Oral Diseases Research, Stomatological Hospital, General Hospital of Ningxia Medical University, Yinchuan 750004, China
  • Received:2025-03-01 Revised:2026-04-24 Online:2026-07-01 Published:2026-06-25
  • Contact: Jian Ma
  • Supported by:
    Key Research and Development Program of Ningxia Hui Autonomous Region(2022BEG03159)

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摘要：

唇腭裂是口腔颌面部常见的先天性畸形，其中非综合征型唇腭裂占大多数，其发生受遗传和环境因素的共同影响。ARHGAP29基因在非综合征型唇腭裂的发病机制中发挥着关键作用。ARHGAP29通过调控细胞骨架的稳定性、细胞迁移和增殖等生物学过程参与颅面部的正常发育，通过调节Rho GTP酶信号通路和Wnt信号通路等途径发挥其生物学功能。本文对ARHGAP29的基因结构、在颅面部发育中的表达和功能、不同人群中ARHGAP29的突变以及与其他基因的相互作用等进行综述，为深入理解唇腭裂的致病机制提供理论依据。

关键词: ARHGAP29基因, 非综合征型唇腭裂, 基因突变, 信号通路

Abstract:

Cleft lip and palate (CL/P) is a prevalent congenital malformation of the craniofacial region, with non-syndromic cleft lip and palate (NSCL/P) representing the majority of cases. The development of NSCL/P is influenced by a combination of genetic and environmental factors. ARHGAP29 gene plays a pivotal role in the pathogenesis of NSCL/P. ARHGAP29 regulates biological processes such as cytoskeletal stability, cell migration, and proliferation, and it contri-butes to normal craniofacial development. This gene likely exerts its function through signaling pathways, including Rho GTPase and Wnt pathways. This review highlights the findings about ARHGAP29, focusing on its gene structure, expression and role in craniofacial development, as well as its mutations in various populations and its interactions with other genes. These insights are essential for understanding the pathogenesis of CL/P.

Key words: ARHGAP29, non-syndromic cleft lip with or without cleft palate, gene mutation, signaling pathway

中图分类号: 

  • R782.2

表 1

ARHGAP29 基因的突变谱"

年份研究类型样本含量/人研究方法样本来源突变位点疾病亚型突变类型参考文献
DNA突变位点蛋白质突变位点

2012

群体研究

病例组770，

对照组516

外显子测序

菲律宾

c.62_63delCTp.S21Yfs*20NSCLP移码突变[13]
c.76A>Gp.Thr26AlaNSCLO错义突变
c.3764G>Ap.Asp1255GNSCL/P错义突变
c.888G>Cp.Arg296SerNSCL/P错义突变
c.976A>Tp.Lys326XNSCLP终止突变
c.1252G>Ap.Val418IleNSCL/P错义突变
c.3604G>Tp.Val1202LeuNSCL/P错义突变
c.1847G>Ap.Arg616HisNSCL/P错义突变
c.1865C>Tp.Thr622MetNSCLP错义突变
c.2494G>Ap.Ala832ThrNSCLO错义突变
c.2533A>Gp.Ile845ValNSCLP错义突变
c.3764G>Ap.Asp1255GNSCL/P错义突变

2012

群体研究

病例组280，

对照组456

外显子测序

美国

c.2017T>Gp.Phe673ValNSCL/P错义突变[13]
c.3023G>Ap.Arg1008LysNSCL/P错义突变
c.3425G>Ap.Arg1142GlnNSCL/P错义突变
c.3764G>Ap.Asp1255GNSCL/P错义突变
c.137A>Gp.Lys46ArgNSCLP错义突变
c.1252G>Ap.Val418IleNSCL/P错义突变
c.2864G>Ap.Arg955HisNSCL/P错义突变
c.3604G>Tp.Val1202LeuNSCL/P错义突变
2014群体研究

病例组60，

对照组60

外显子测序印度c. 94A>Tp.Asp32ValNSCLP终止突变[27]
2014群体研究

埃塞俄比亚80，

尼日利亚140

外显子测序埃塞俄比亚、尼日利亚c.2864G>Ap.Arg955HisNSCLP错义突变[28]
c.2738C>Ap.Ser913LeuNSCLO错义突变

2017

群体研究

病例组188（巴西173，英国15）

对照组1 210

下一代测序

巴西、英国

c.3339T>Gp.I1113MNSCL/P错义突变[29]
c.3326_3328 delCAAp.T1109delNSCL/P框内缺失
c.2617C>Tp.R873CNSCL/P错义突变
c.2393G>Ap.R798QNSCL/P错义突变
c.2109+1G>A-NSCL/P剪接位点突变
c.1576+1G>A-NSCL/P剪接位点突变
c.1475C>Ap.S492*NSCL/P终止突变
c.G1252Ap.V418INSCL/P错义突变
c.698-1G>C-NSCL/P剪接位点突变
c.91C>Tp.L31FNSCL/P错义突变
2017家系研究家系（病例5/对照5）外显子测序欧洲c.1654T>Cp.Ser552ProNSCPo错义突变[20]
2020家系研究

家系

（病例4/对照12）

外显子测序中国c.2615C>Tp.A872VNSCLP错义突变[25]
2022家系研究家系（连续2胎患病，病例4/对照2）外显子测序中国c.1920+1G>A-NSCLP，NSCLO剪接位点突变[26]

图 1

ARHGAP29通过Rho信号通路发挥作用的假设模型"

[1] Salari N, Darvishi N, Heydari M, et al. Global prevalence of cleft palate, cleft lip and cleft palate and lip: a comprehensive systematic review and Meta-analysis[J]. J Stomatol Oral Maxillofac Surg, 2022, 123(2): 110-120.
[2] Saad AN, Parina RP, Tokin C, et al. Incidence of oral clefts among different ethnicities in the state of california[J]. Ann Plast Surg, 2014, 72(): S81-S83.
[3] Yow M, Jin AZ, Yeo GSH. Epidemiologic trends of infants with orofacial clefts in a multiethnic country: a retrospective population-based study[J]. Sci Rep, 2021, 11: 7556.
[4] Yan SJ, Yu QX, Zhou H, et al. Association of prenatal cleft lip and palate ultrasound abnormalities with copy number variants at a single Chinese tertiary center[J]. Ital J Pediatr, 2024, 50: 152.
[5] Yu YQ, Zuo X, He M, et al. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity[J]. Nat Commun, 2017, 8: 14364.
[6] Feng H, Wei B, Xie XD, et al. The potential up-regulation risk of 3' UTR SNP (rs10787760 G>A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population[J]. Gene, 2024, 922: 148458.
[7] Beaty TH, Murray JC, Marazita ML, et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[J]. Nat Genet, 2010, 42(6): 525-529.
[8] Mukhopadhyay N, Feingold E, Moreno-Uribe L, et al. Genome-wide association study of non-syndromic orofacial clefts in a multiethnic sample of families and controls identifies novel regions[J]. Front Cell Dev Biol, 2021, 9: 621482.
[9] 杨怡欣, 李沐嘉, 郑谦, 等. 后全基因组关联研究时代非综合征型唇腭裂遗传学及易感基因功能学研究策略[J]. 中华口腔医学杂志, 2024, 59(6): 634- 639.
Yang YX, Li MJ, Zheng Q, et al. Genetic and functional research strategies of non-syndromic cleft lip with or without cleft palate in the post genome-wide association study era[J]. Chin J Stomatol, 2024, 59(6): 634-639.
[10] 王世奎, 宋庆高, 兰雪娇. MAFB基因多态性与非综合征型唇腭裂的研究进展[J]. 口腔疾病防治, 2021, 29(1): 61-64.
Wang SK, Song QG, Lan XJ, et al. Research progress on MAFB gene polymorphism and nonsyndromic cleft lip and palate[J]. J Prevent Treat Stomatol Dis, 2021, 29(1): 61-64.
[11] Zhang SD, You Y, Yao ML, et al. Review on the role of IRF6 in the pathogenesis of non-syndromic orofacial clefts[J]. Chin J Dent Res, 2024, 27(1): 29-38.
[12] Mukhopadhyay N, Feingold E, Moreno-Uribe L, et al. Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes[J]. Genet Epidemiol, 2022, 46(3/4): 182-198.
[13] Leslie EJ, Mansilla MA, Biggs LC, et al. Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22[J]. Birth Defects Res A clin Mol Teratol, 2012, 94(11): 934-942.
[14] Saras J, Franzén P, Aspenström P, et al. A novel GTPase-activating protein for rho interacts with a PDZ domain of the protein-tyrosine phosphatase PTPL1[J]. J Biol Chem, 1997, 272(39): 24333-24338.
[15] Chi DD, Wang YM, Yu LL, et al. Arhgap29 deficiency causes EEC like syndrome in mice[J]. Genes Dis, 2025, 12(4): 101404.
[16] Ranji P, Pairet E, Helaers R, et al. Four putative pathogenic ARHGAP29 variants in patients with non-syndromic orofacial clefts (NsOFC)[J]. Eur J Hum Genet, 2025, 33(1): 38-43.
[17] Paul BJ, Palmer K, Sharp JC, et al. ARHGAP29 mutation is associated with abnormal oral epithelial adhesions[J]. J Dent Res, 2017, 96(11): 1298-1305.
[18] 阮文彦. Arhgap29对小鼠腭突间充质细胞增殖、迁移和凋亡的影响[D]. 银川: 宁夏医科大学, 2022.
Ruan WY. Effects of Arhgap29 on mouse EPM cells proliferation,migration and apoptosis[D]. Yinchuan: Ningxia Medical University, 2022.
[19] 胡晓, 李叶扬, 梁岷, 等. 维甲酸改变腭突发育关键时期细胞增殖和凋亡导致腭裂[J]. 中华整形外科杂志, 2016, 32(3): 220-224.
Hu X, Li YY, Liang M, et al. Induced cleft palat by retinoic acid through altering the cell proliferation and apoptosis at the key stages of palatal development[J]. Chin J Plast Surg, 2016, 32(3): 220-224.
[20] Liu H, Busch T, Eliason S, et al. Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate[J]. Birth Defects Res A Clin Mol Teratol, 2017, 109(1): 27-37.
[21] Rhea L, Reeb T, Adelizzi E, et al. ARHGAP29 promotes keratinocyte proliferation and migration in vitro and is dispensable for in vivo wound healing[J]. Dev Dyn, 2025, 254(4): 310-329.
[22] Xu K, Sacharidou A, Fu S, et al. Blood vessel tubulogenesis requires Rasip1 regulation of GTPase signa-ling[J]. Dev Cell, 2011, 20(4): 526-539.
[23] Post A, Pannekoek WJ, Ross SH, et al. Rasip1 me-diates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29[J]. Proc Natl Acad Sci USA, 2013, 110(28): 11427-11432.
[24] Tagashira T, Fukuda T, Miyata M, et al. Afadin facilitates vascular endothelial growth factor-induced network formation and migration of vascular endothelial cells by inactivating rho-associated kinase through ArhGAP29[J]. Arterioscler Thromb Vasc Biol, 2018, 38(5): 1159-1169.
[25] Tang JX, Xiao XS, Wang K, et al. Identification of a novel variant of ARHGAP29 in a Chinese family with nonsyndromic cleft lip and palate[J]. Biomed Res Int, 2020: 8790531.
[26] Yu QX, Deng Q, Fu F, et al. A novel splicing mutation of ARHGAP29 is associated with nonsyndromic cleft lip with or without cleft palate[J]. J Matern Fetal Neonatal Med, 2022, 35(13): 2499-2506.
[27] Chandrasekharan D, Ramanathan A. Identification of a novel heterozygous truncation mutation in exon 1 of ARHGAP29 in an Indian subject with nonsyndromic cleft lip with cleft palate[J]. Eur J Dent, 2014, 8(4): 528-532.
[28] Butali A, Mossey P, Adeyemo W, et al. Rare functio-nal variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population[J]. Am J Med Genet A, 2014, 164(10): 2567-2571.
[29] Savastano CP, Brito LA, Faria ÁC, et al. Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss-of-function vs missense variants[J]. Clin Genet, 2017, 91(5): 683-689.
[30] Letra A, Maili L, Mulliken JB, et al. Further evidence suggesting a role for variation in ARHGAP29 va-riants in nonsyndromic cleft lip/palate[J]. Birth Defects Res A Clin Mol Teratol, 2014, 100(9): 679-685.
[31] Wang Y, Shi J, Zheng Q, et al. Gene-gene interactions between BMP4 and ARHGAP29 among non-syndromic cleft lip only (NSCLO) trios from western Han Chinese population[J]. Int J Clin Exp Pathol, 2020, 13(2): 295-301.
[32] van Eekelen M, Runtuwene V, Masselink W, et al. Pair-wise regulation of convergence and extension cell movements by four phosphatases via RhoA[J]. PLoS One, 2012, 7(4): e35913.
[33] Rahimov F, Nieminen P, Kumari P, et al. High incidence and geographic distribution of cleft palate in Finland are associated with the IRF6 gene[J]. Nat Commun, 2024, 15(1): 9568.
[34] Qiao YT, Chen JX, Lim YB, et al. YAP regulates actin dynamics through ARHGAP29 and promotes metastasis[J]. Cell Rep, 2017, 19(8): 1495-1502.
[35] Shimizu K, Matsumoto H, Hirata H, et al. ARHGAP29 expression may be a novel prognostic factor of cell proliferation and invasion in prostate cancer[J]. Oncol Rep, 2020, 44(6): 2735-2745.
[36] Reynolds K, Kumari P, Sepulveda Rincon L, et al. Wnt signaling in orofacial clefts: crosstalk, pathoge-nesis and models[J]. Dis Model Mech, 2019, 12(2): dmm037051.
[37] Menezes R, Letra A, Kim AH, et al. Studies with Wnt genes and nonsyndromic cleft lip and palate[J]. Birth Defects Res A Clin Mol Teratol, 2010, 88(11): 995-1000.
[38] 陆铖, 王江玥, 贾仲林. 影响非综合征型唇腭裂的环境因素[J]. 华西口腔医学杂志, 2019, 37(5): 547- 550.
Lu C, Wang JY, Jia ZL. Environmental factors of non-syndromic cleft lip and palate[J]. West China J Stomatol, 2019, 37(5): 547-550.
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