SBF1

更新于：2025-05-07

基本信息

别名

DENND7A、Inactive phosphatidylinositol 3-phosphatase 5、MTMR5

+ [4]

简介

Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location (PubMed:12668758). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:20937701). May function as a guanine nucleotide exchange factor (GEF) activating RAB28 (PubMed:20937701). Acts as a suppressor of autophagy in neurons (PubMed:35580604). Together with its binding partner, the phosphatase MTMR2, plays a role in dephosphorylation of phosphoinositides critical for autophagy initiation and autophagosome maturation (PubMed:35580604). Plays a role in positively regulating late-stage radial sorting of large caliber axons, a process leading to myelination by Schwann cells, possibly via regulating endosomal trafficking (By similarity). Inhibits myoblast differentiation in vitro and induces oncogenic transformation in fibroblasts (PubMed:9537414).

关联

100 项与 SBF1 相关的临床结果

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100 项与 SBF1 相关的转化医学

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0 项与 SBF1 相关的专利（医药）

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项与 SBF1 相关的文献（医药）

2025-03-04·Brain Communications

Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3

Article

作者: Dowling, James J ; Geissah, Salma ; Ariaz, Atai ; Lindzon, Jordan ; List, Maia ; Zhao, Mo

AbstractBiallelic loss of expression/function variants in MTMR5/SBF1 cause the inherited peripheral neuropathy Charcot-Marie-Tooth type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying Charcot-Marie-Tooth type 4B3, and despite its severe clinical presentation, currently no disease-modifying therapies. A key barrier to the study of Charcot-Marie-Tooth type 4B3 is the lack of pre-clinical models that recapitulate the clinical and pathologic features of the disease. To address this barrier, we generated a zebrafish Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 mutant line with a full gene deletion of mtmr5. Resulting homozygous deletion zebrafish are born at normal Mendelian ratios and have preserved motor function. However, starting by 10 days post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume. These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination changes reminiscent of the nerve pathology in human Charcot-Marie-Tooth type 4B3. Importantly, RNA sequencing from brain-enriched samples identifies novel disease pathways including transcriptional changes in genes responsible for neurogenesis, chromatin remodelling/organization, and synaptic membrane homeostasis. Overall, our mtmr5 knockout zebrafish mirror genetic, clinical and pathologic features of human Charcot-Marie-Tooth type 4B3. As such, it represents a first pre-clinical model to phenocopy the disease, and an ideal tool for future studies on disease pathomechanism(s) and therapy development.

2024-12-01·Stem Cell Research

Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene

Article

作者: Saporta, Mario A. ; Jacobs, Elizabeth H ; Schatzman Raposo, Jacquelyn ; Jacobs, Elizabeth H. ; Alkuraya, Fowzan S. ; Nafissi, Shahriar ; Alkuraya, Fowzan S ; Zuchner, Stephan ; Saporta, Mario A ; Scardamaglia, Annarita ; Houlden, Henry

Myotubularin-Related Protein 5 (MTMR5) is an inactive, poorly characterized D3-phosphatidylinositol phosphatase. Mutations in MTMR5 have been linked to Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3), a rare, early-onset, recessive peripheral neuropathy. Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations. Current MTMR5 ^-/- animal models do not clearly link Sbf1 mutations to severe neuropathy, so such a resource is highly desired to further elucidate the relationship between MTMR5 dysfunction and peripheral nerve degeneration.

2023-10-01·Translational Pediatrics

Whole-exome sequencing revealed novel genetic alterations in patients with tetralogy of Fallot

Article

作者: Mei, Huaxian ; Liu, Manli ; Wu, Jing ; Zhang, Songsong ; Pan, Yu

BackgroundThe most prevalent cyanotic congenital heart disease (CHD) phenotype is tetralogy of Fallot (TOF). Rare genetic variations have been identified as significant risk factors for CHD. Thus, this research sought to identify the pathogenic variations and molecular etiologies of TOF.MethodsThis study employed whole-exome sequencing (WES) and Sanger sequencing to identify pathogenic variations in DNA samples from patients with TOF. The pathogenicity of the variations was predicted using an in-silico approach.ResultsWe enrolled 17 patients with TOF in this study. Among these patients, 14 had mutations in TOF-related genes, including GJB2, TBX15, CTNS, SPINK1, GATA6, PRIMOL, GDF15, SLC17A9, AIFM1, FOXC2, KLF13, ABCA4, CPA6, FKBP10, ASPA, SBF1, HBA2, IGLL1, GNE, and KLHL10. We also gathered WES data from three participants without TOF, who comprised the control group, but no variations were found in the indicated genes. Further analysis showed that the patients with FKBP10 and GNE variants had more serious clinical symptoms. Sanger sequencing confirmed that the two variants were heterozygous in TOF patients.ConclusionsWe identified several genetic variants associated with TOF and confirmed that FKBP10 and GNE variants were associated with TOF severity. The findings of this study help researchers and clinicians on genetic counseling with the verification of the potential of WES in detecting TOF and help implement early interventions for patients with TOF.

项与 SBF1 相关的新闻（医药）

2024-02-06

·生物探索

Nat Commun | 复旦大学丁琛/陈治宇通过血浆蛋白质谱揭示结直肠癌诊断和西妥昔单抗治疗反应的生物标志物多样性

引言西妥昔单抗治疗是结直肠癌（CRC）的主要治疗方法，但耐药性限制了其有效性。2024年2月1日，复旦大学丁琛及陈治宇共同通讯在Nature Communications (IF 16.6)发表题为“Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer”的研究论文，该研究对来自147名接受西妥昔单抗多疗程治疗的CRC患者（CRC）和90名健康对照（HC）的641份血浆样本进行了纵向和深度蛋白质组学分析。COL12A1、THBS2、S100A8和S100A9作为潜在蛋白进行筛选，以在血浆和组织验证队列中区分CRC和HC。该研究确定了潜在的生物标志物（RRAS2、MMP8、FBLN1、RPTOR 和 IMPDH2）用于初始疗效预测。在纵向研究中，确定了具有不同波动的两个集群，并构建了高精度的模型来预测纵向应答，并在独立队列中进一步验证。该研究揭示了不同生物标志物在肿瘤诊断、西妥昔单抗首疗程和多疗程治疗的初始和纵向疗效预测方面的异质性，可能最终有助于CRC的监测和干预策略。结直肠癌（CRC）是全球第三大常见癌症。对于结直肠癌患者，筛查已被证明可以降低平均风险女性和平均风险男性的癌症死亡率。然而，疾病进展缓慢且无症状，使得早期诊断具有挑战性，这严重降低了及时发现和干预疾病的机会。因此，当务之急是探索潜在的生物标志物，以区分CRC患者和健康对照者，从而提高无创准确的诊断策略。大约一半的结直肠癌患者死于转移性疾病。目前不可切除结直肠癌患者的一线治疗标准是化疗联合单克隆抗体（mAb）。经过20多年的转化和临床研究，EGFR家族及其细胞内信号通路仍然是CRC靶向分子治疗的关键。表皮生长因子受体(EGFR, HER1)是一种具有酪氨酸激酶酶活性的细胞膜生长因子受体家族中的生长因子受体。西妥昔单抗是一种针对EGFR的嵌合单克隆抗体，通过阻断配体结合区、阻断配体诱导的EGFR酪氨酸激酶激活和随后导致癌细胞增殖的信号转导事件，以高亲和力特异性结合 EGFR。一项随机试验（CO.17）显示，在对晚期化疗无反应的CRC患者中，西妥昔单抗比单独使用最佳支持治疗改善了总生存期和无进展生存期，并更好地保留了生活质量。虽然约85%的CRC患者表达EGFR，但西妥昔单抗耐药的情况常见，在第一次评估时，超过50%的接受治疗患者已发生疾病进展。因此，有必要找到西妥昔单抗首次治疗反应的潜在预测性生物标志物。KRAS激活突变的存在被发现是CRC抗EGFR治疗的第一个预测性阴性生物标志物。已经研究了一系列可能有助于预测对EGFR抑制剂反应的潜在生物标志物。此外，获得性耐药性不可避免地出现，所有患者都发生疾病进展，这限制了药物的临床疗效。获得性耐药性的出现使患者无法长期受益；然而，获得性耐药性的早期预警仍不清楚。因此，在CRC患者的每个治疗过程中进行动态抽样是必要的，并有助于很好地理解西妥昔单抗治疗期间与治疗反应相关的动态轨迹。基于质谱（MS）的血浆蛋白质组学已成功应用于疾病诊断和疾病中蛋白质变化轨迹的表征，表明它是在这种易于获取的血浆样品中发现生物标志物的最佳技术。在该研究中，收集了来自116例接受西妥昔单抗连续多个疗程治疗的结直肠癌患者(CRC)和66名健康对照(HC)的540份血浆样本(血浆发现队列)，来自31例CRC和24例HC的101份血浆样本(血浆验证队列)，以及来自31例治疗初期CRC的31份肿瘤组织样本和27份配对的癌旁组织(NAT)。研究对血浆蛋白质组进行了无偏倚的全面分析，以寻找CRC诊断和西妥昔单抗治疗反应的生物标志物。首先对接受过治疗的CRC患者和健康对照者的蛋白质组谱进行了比较蛋白质组学分析。结果显示，治疗前的CRC患者具有细胞外基质组织（ECM）的特征。研究鉴定出主要参与ECM通路的COL12A1、THBS2、S100A8和S100A9蛋白，可作为有效的生物标志物，在独立的组织和血浆验证队列中得到了进一步验证。此外，研究者还在更广泛的CRC患者人群中验证了这4种蛋白的预测效果，但不限于RAS野生型CRC患者或转移性CRC患者。该研究还探索了4种蛋白能很好地区别CRCs和HCs，但不能区分其他癌症和非恶性疾病的患者，表明这4种蛋白对CRC诊断具有相对特异性。然后，研究对治疗前结直肠癌患者的蛋白质组谱进行了共识聚类分析，确定了3种具有不同生物过程特征的蛋白质组亚型，并与不同的治疗反应相关。RRAS2、MMP8、FBLN1、RPTOR和IMPDH2等通路关键调控因子可作为西妥昔单抗首次治疗反应预测的生物标志物，用于区分敏感患者和非敏感患者，并在独立的组织和血浆验证队列中进行了验证。CRC队列和健康对照的血浆蛋白质组学分析总结（Credit: Nature Communications）此外，研究分析了一个纵向队列，以确定与西妥昔单抗治疗反应相关的具有动态变化的蛋白质。最后，采用logistic回归策略构建由IDH3G、MDN1、KLC4、MYL9、SBF1和HTRA3组成的预测模型，对多疗程西妥昔单抗治疗的反应预测精度较高。该预测模型的稳健性在独立血浆队列中得到了进一步验证。该研究提供了西妥昔单抗治疗过程中患者血浆蛋白的动态变化，并确定了用于肿瘤诊断、初始疗效预测和纵向疗效预测的潜在生物标志物，揭示了这些不同生物标志物在结直肠癌临床管理中的异质性。原文链接https://doi.org/10.1038/s41467-024-44911-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

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