Tubb4a-flox 基因敲除小鼠

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产品名称

Tubb4a-flox 基因敲除小鼠

产品编号

S-CKO-06490

品系全称

C57BL/6JCya-Tubb4aem1flox/Cya

品系背景

C57BL/6JCya

品系编号

CKOCMP-22153-Tubb4a-B6J-VA

品系状态

使用本品系发表的文献需注明: Tubb4a-flox 基因敲除小鼠 mice (Strain S-CKO-06490) were purchased from Cyagen.
交付类型
周龄
性别
基因型
数量
cKO小鼠库模型

基本信息

基因研究概述

质控标准

基因
基因全称
tubulin, beta 4A class IVA
基因别称
M(beta)4,Tubb,Tubb4
染色体号
Chr 17 (Mouse)
转录本 ID
NCBI: NM_009451.4 | Ensembl: ENSMUST00000071135
修饰方式
条件性基因敲除
靶向范围
Exon 2~3
敲除长度
~848 bp
品系说明
该品系是基于策略设计时的数据库信息制作而成,建议您在购买前查询最新的数据库和相关文献,以获取最准确的表型信息。
表型提示
MGI:107848Mice homozygous for a null allele do not exhibit a phenotype. However, mice with an N414K mutation exhibit ataxia, reduction of myelination, cerebellum atrophy and granule cell neuron degeneration.
Tubb4a,也称为β微管蛋白4A,是一种编码β-微管蛋白的基因。β-微管蛋白是细胞骨架的组成成分,参与细胞分裂、细胞运输、细胞形态维持和细胞信号传导等多种生物学过程。Tubb4a基因突变可导致多种疾病,包括低髓鞘化脑白质营养不良(H-ABC)、肌张力障碍(DYT-TUBB4A)和癫痫性脑病等[1,2,3,4,5,6,7,8,9,10]。

H-ABC是一种罕见的遗传性脑白质营养不良,主要表现为基底节和小脑萎缩。Tubb4a基因突变导致的H-ABC患者,其临床和影像学特征为进行性痉挛性瘫痪、轻度小脑共济失调和轻度认知功能障碍等。神经影像检查显示,患者双侧中脑腹侧、内囊后肢、侧脑室后角旁及半卵圆中心对称分布斑片状稍长T(2)高信号影,及液体衰减反转恢复(FLAIR)序列呈稍高信号影。基因检测发现,在TUBB4A基因外显子区域有一处错义杂合突变位点c.70G>A,导致氨基酸改变(p.G24R,甘氨酸>精氨酸),突变致病性预测软件分析显示其为有害突变[1]。

DYT-TUBB4A是一种以肌张力障碍为主的遗传性疾病,常伴有发声困难。Tubb4a基因突变导致的DYT-TUBB4A患者,其临床表现为喉肌张力障碍、颈肌张力障碍和肢体肌张力障碍等。基因检测发现,DYT-TUBB4A患者中存在多种TUBB4A基因突变,如p.R2G、p.Q424H、p.R2W和p.D249N等。这些突变在分子和细胞水平上表现出不同的致病效应,部分反映了DYT-TUBB4A的表型多样性[3]。

Tubb4a基因突变还可以导致癫痫性脑病,如婴儿痉挛症和Lennox-Gastaut综合征等。Tubb4a基因突变导致的癫痫性脑病患者,其临床表现包括早期难治性癫痫发作、发育迟缓或倒退、智力障碍等。基因检测发现,患者存在TUBB4A基因的错义突变,如p.R156C等。这些突变对TUBB4A蛋白的结构和稳定性具有潜在的破坏作用[4]。

此外,Tubb4a基因突变还与黑色素瘤的发生发展密切相关。Tubb4a基因在黑色素瘤组织中表达上调,与黑色素瘤患者的生存时间呈正相关。基因功能实验表明,抑制Tubb4a基因表达可以抑制黑色素瘤细胞的增殖和迁移,促进黑色素瘤细胞的凋亡,并阻断黑色素瘤细胞周期[5,7]。

综上所述,Tubb4a基因突变可导致多种疾病,包括H-ABC、DYT-TUBB4A、癫痫性脑病和黑色素瘤等。Tubb4a基因突变导致的疾病具有不同的临床表型和分子机制,这为疾病的治疗和预防提供了新的思路和策略。未来,深入研究Tubb4a基因突变的致病机制和生物学功能,有助于开发针对Tubb4a基因突变相关疾病的新疗法。

参考文献:
1. Du, Y, Li, C, Guo, J, Li, Z Y, Zhang, W. . [A report of atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum caused by a de novo mutation in tubulin beta 4A (TUBB4A) gene and literature review]. In Zhonghua nei ke za zhi, 56, 433-437. doi:10.3760/cma.j.issn.0578-1426.2017.06.009. https://pubmed.ncbi.nlm.nih.gov/28592043/
2. Duncan, Ian D, Bugiani, Marianna, Radcliff, Abigail B, van der Knaap, Marjo S, Svaren, John. 2017. A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. In Annals of neurology, 81, 690-702. doi:10.1002/ana.24930. https://pubmed.ncbi.nlm.nih.gov/28393430/
3. Krajka, Victor, Vulinovic, Franca, Genova, Mariya, Klein, Christine, Rakovic, Aleksandar. 2022. H-ABC- and dystonia-causing TUBB4A mutations show distinct pathogenic effects. In Science advances, 8, eabj9229. doi:10.1126/sciadv.abj9229. https://pubmed.ncbi.nlm.nih.gov/35275727/
4. Ben Jdila, Marwa, Kammoun, Fatma, Abdelmaksoud-Dammak, Rania, Triki, Chahnez, Fakhfakh, Faiza. 2023. Mutation in the β-tubulin gene TUBB4A results in epileptic encephalopathy associated with hypomyelinated leucodystrophy: Unexpected findings reveal genetic mosaicism. In International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 83, 532-545. doi:10.1002/jdn.10284. https://pubmed.ncbi.nlm.nih.gov/37529938/
5. Zhang, Jiaqi, Zhang, Yu, Liu, Jun, Yun, Yifei, Cao, Yan. . Identification of TUBB4A as a Prognostic Biomarker of Melanoma by Transcriptomic Data and In Vitro Experiments. In Technology in cancer research & treatment, 22, 15330338231184842. doi:10.1177/15330338231184842. https://pubmed.ncbi.nlm.nih.gov/37439014/
6. Bally, Julien F, Camargos, Sarah, Oliveira Dos Santos, Camila, de Carvalho Aguiar, Patricia, Lang, Anthony E. 2020. DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations. In Neurology, 96, e1887-e1897. doi:10.1212/WNL.0000000000010882. https://pubmed.ncbi.nlm.nih.gov/32943487/
7. Chen, Guanghua, Yan, Jia. . Dysregulation of SNHG16(lncRNA)-Hsa-Let-7b-5p(miRNA)-TUBB4A (mRNA) Pathway Fuels Progression of Skin Cutaneous Melanoma. In Current protein & peptide science, 23, 791-809. doi:10.2174/1389201023666220928120902. https://pubmed.ncbi.nlm.nih.gov/36173063/
8. Vulinovic, Franca, Schaake, Susen, Domingo, Aloysius, Lohmann, Katja, Klein, Christine. 2017. Screening study of TUBB4A in isolated dystonia. In Parkinsonism & related disorders, 41, 118-120. doi:10.1016/j.parkreldis.2017.06.001. https://pubmed.ncbi.nlm.nih.gov/28655586/
9. Garg, Divyani, Holla, Vikram V, Ganguly, Jacky, Srivastava, Achal Kumar, Pal, Pramod Kumar. 2024. Expanding the phenotypic and genotypic spectrum of DYT-TUBB4A with seven patients from India. In Parkinsonism & related disorders, 124, 107012. doi:10.1016/j.parkreldis.2024.107012. https://pubmed.ncbi.nlm.nih.gov/38762926/
10. Blumkin, Lubov, Halevy, Ayelet, Ben-Ami-Raichman, Dominique, Lerman-Sagie, Tally, Leshinsky-Silver, Esther. 2014. Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene. In Neurogenetics, 15, 107-13. doi:10.1007/s10048-014-0392-2. https://pubmed.ncbi.nlm.nih.gov/24526230/