更新于：2024-09-19

B3GALT6

更新于：2024-09-19

基本信息

别名

B3GALT6、beta-1,3-galactosyltransferase 6、Beta-1,3-GalTase 6

+ [6]

简介

Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue. Has a preference for galactose-beta-1,4-xylose that is found in the linker region of glycosaminoglycans, such as heparan sulfate and chondroitin sulfate. Has no activity towards substrates with terminal glucosamine or galactosamine residues.

关联

100 项与 B3GALT6 相关的临床结果

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100 项与 B3GALT6 相关的转化医学

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0 项与 B3GALT6 相关的专利（医药）

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106

项与 B3GALT6 相关的文献（医药）

2024-06-01·European Journal of Medical Genetics

Prenatal and neonatal phenotype of Larsen of La Réunion Island syndrome (B4GALT7-linkeropathy)

Article

作者: Calaya, Anais ; Randrianaivo, Hanitra ; Munier, Patrick ; Dumont, Coralie ; Celse, Tristan ; Irabé, Mireille ; Laurens, Tiffany ; Payet, Frédérique ; Spodenkiewicz, Marta ; Doray, Bérénice ; Bertaut-Nativel, Bénédicte ; Morel, Godelieve ; Jacquemont, Marie-Line ; Guilly, Suzie ; Dospeux, Jessica ; Alessandri, Jean-Luc ; Ferroul, Fanny ; Huby, Thomas ; Boumahni, Brahim ; Rémy, Mathilde

Larsen of La Réunion Island syndrome (LRS) is an autosomal recessive condition associated with multiple large joint dislocations, clubfeet, severe dwarfism, and distinctive facial features. LRS is caused by a recurrent homozygous variant in B4GALT7 gene with a founder effect in La Réunion population. Proteoglycans (PG) that are a major component of the extracellular matrix, are composed of a core protein connected to a glycosaminoglycans side chain via a tetrasaccharide linker region. B4GALT7 encodes galactosyltransferase I, one of the enzymes involved in the biosynthesis of the linker region. Conditions caused by pathogenic biallelic variants in genes implicated in the synthesis of the tetrasaccharide linker of PG are known as linkeropathies. Prenatal features are rarely described in this group of chondrodysplasias. We present a series of 12 unpublished patients having LRS and describe the perinatal phenotype. All the patients had a prenatal growth restriction with brevity of limbs. The other features revealed by ultrasounds were increased nuchal translucency at 10-12 weeks of gestation (50 %), feet abnormalities (clubfeet or metatarsus varus) (25 %), dislocation affecting at least one large joint (elbow, knee, wrist) (25 %). Bilateral bowing of femora was noted for two fetuses. Fibular hypertrophy was noted for one fetus. Prenatal helical computed tomography (CT) performed in three pregnancies showed additional data such as bowing of the forearm bones, proximal radio-ulnar synostosis, or dislocation of large joints. Prenatal sonographic and helical CT findings led to the prenatal diagnosis of LRS in four patients. We confirm that the neonatal clinical picture of LRS has an important overlap with that reported in patients with B4GALT7 deficiency outside La Réunion Island and other linkeropathies. The core of the phenotypic spectrum combines low birth height, micromelia, hypermobility, dislocation of at least one large joint, facial features with prominent eyes, microstomia, depressed nasal bridge, and midface hypoplasia. Other clinical features include clubfeet (33%), bifid thumb in one patient, and cardiac abnormalities in two patients. Radiological findings include radio-ulnar synostosis (75%), metaphyseal flaring, precocious carpal ossification, and a Swedish key appearance of the proximal femora. Finally, we also report radiological features rarely described in B4GALT7-linkeropathies, including bowing of the femora and fibular hypertrophy. Our results confirm the phenotypic continuum of LRS within linkeropathies with some additional findings, including a high frequency of clubfeet usually described in B3GALT6-linkeropathies, the presence of congenital heart diseases usually described in B3GAT3-linkeropathies, and a high frequency of metaphyseal flaring usually reported in B3GALT6 or XITLT1-linkeropathies. This is the first study that describes the perinatal phenotype in a cohort of patients with LRS. This study can help improve the prenatal diagnosis of the linkeropathies and add this group of conditions to the differential diagnosis of chondrodysplasias with multiple dislocations. In view of the founder effect for LRS in La Réunion Island, this disease should be suspected in fetuses with growth restriction and micromelia. Thus in case of LOH which include B4GALT7 identified in SNP-array, we recommend performing a targeted Sanger sequencing for the recurrent mutation c.808C > T; p. (Arg270Cys).

2024-01-01·Cancer Cell

B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling

Article

作者: Escobar-Aguirre, Matias ; Choudhury, Biswa ; Benz, Brian A ; Toriumi, Takashi ; Marino, Francesco E ; Pan, Tien-Chi ; Belka, George K ; Lawrence-Paul, Matthew R ; Sterner, Christopher J ; Esko, Jeffrey D ; Lu, Michelle ; Pant, Dhruv K ; Chodosh, Lewis A ; Sreekumar, Amulya

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.

2023-12-31·Aging

Mapping of the gene network that regulates glycan clock of ageing

Article

作者: Pribić, Tea ; Lauc, Gordan ; Wuhrer, Manfred ; Gieger, Christian ; Cuadrat, Rafael R C ; Sharapov, Sodbo Z ; Tominac, Petra ; Akker, Erik van den ; Beekman, Marian ; Hayward, Caroline ; Mijakovac, Anika ; Pučić-Baković, Maja ; Radovani, Barbara ; Štambuk, Tamara ; Polasek, Ozren ; Štambuk, Jerko ; Zoldoš, Vlatka ; Frkatović-Hodžić, Azra ; Trbojević-Akmačić, Irena ; Nostaeva, Arina ; Krištić, Jasminka ; Spector, Tim D ; Miškec, Karlo ; Wittenbecher, Clemens ; Schulze, Matthias B ; Vučković, Frano ; Fischer, Krista ; Rudman, Najda ; Gudelj, Ivan ; Haller, Toomas ; Mangino, Massimo ; Köttgen, Anna ; Landini, Arianna ; Vojta, Aleksandar ; Wilson, James F ; Keser, Toma ; Aulchenko, Yurii S ; Sharma, Sapna ; Klarić, Lucija ; Li, Yong

Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.

项与 B3GALT6 相关的新闻（医药）

2024-02-11

·药明康德

1月，11款创新靶点值得关注（附PDF下载）

▎药明康德内容团队编辑近三年，FDA批准的新药里具有创新机制的药物占比均超过一半。由于基于靶点的筛选是过去几十年新药研发的主要方式，这些创新药物的起点往往都是相关靶点的发现和验证。这也意味着医药行业的不断创新仰赖对新靶点及其生物学机理的不断挖掘。正如多位嘉宾在药明康德BOLD系列论坛中指出的那样，很多“容易的靶点”已经转化为了创新疗法，如今的新药发现公司需要探索更为复杂、更难治疗的疾病，而这个过程依赖于对于靶点及其生物学的深度认知，也需要前沿科技的更多进步。药明康德内容团队盘点了2024年1月发布于国际知名科研期刊中的潜力靶点，以供各位医药界的朋友们参考。这些潜力靶点涵盖癌症、中枢神经系统疾病、心血管、罕见病等多个方向，有的是新的肿瘤合成致死靶点，有的为罕见病提供了全新治疗方案，都具有潜在转化价值。在这篇文章中，我们优选3个值得关注的靶点做详细报道。点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整11个靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告靶点：APOE3ch应用：诠释一种拮抗阿尔茨海默症的基因突变机理期刊 / PMID：《细胞》 / 38086389发现：一个病例报告研究显示APOE3 Christchurch（APOE3ch）突变纯合携带者对PSEN1-E280A突变引起的常染色体显性阿尔茨海默病（AD）具有抵抗力。本论文的研究人员构建了人源化APOE3ch敲入小鼠。与病例报告类似，在该小鼠模型里APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少。淀粉样蛋白反应减少与斑块周围的小胶质细胞反应增强。这些结果显示APOE3ch影响小胶质细胞对Aβ斑块的反应，抑制Aβ诱导的tau蛋白播种和扩散，也为Aβ诱导的tau蛋白病变提供了新的药物研发思路。▲APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少（图片来源：参考资料[1]）靶点：B3GALT6应用：清除导致复发的难治性残留肿瘤细胞期刊 / PMID：Cancer Cell / 38065100发现：无法治愈的复发是乳腺癌等肿瘤致死的主要原因，这种复发被认为来自休眠的、难治性残留肿瘤细胞（RTC）播种。因此，了解RTC存活的机制对改善癌症治疗至关重要。在这篇论文里，作者通过体内CRISPR-Cas9筛选细胞休眠相关的候选基因，确定半乳糖基转移酶B3GALT6是RTC适应性的功能调节因子。B3GALT6是糖胺聚糖（glycosaminoglycan，GAG）与蛋白质连接，生成蛋白聚糖所必需的代谢酶，种系功能缺失会导致骨骼发育不良。而研究人员发现B3GALT6介导的硫酸乙酰肝素GAG生物合成可预测肿瘤患者预后不良。机理上，B3GALT6-硫酸乙酰肝素/HS6ST1-乙酰肝素6-O-硫酸化/FGF1-FGFR2信号通路能提高休眠RTC的存活率，促进复发。该研究表明B3GALT6与癌症有关，抑制B3GALT6相关通路，包括抑制FGFR2是一种潜在的根除休眠RTC，预防复发的手段。▲B3GALT6在微环境诱导的肿瘤休眠模型中促进肿瘤细胞存活及生长（图片来源：参考资料[2]）靶点：KMT2E应用：肺动脉高压关键靶点期刊 / PMID：Science Translational Medicine / 38198571发现：肺动脉高压（PAH）是一种由依赖缺氧诱导因子（HIF）的血管功能障碍驱动的疾病，HIF-2α促进邻近基因KMT2E-AS1和KMT2E的表达。在功能上，KMT2E-AS1是一种长非编码RNA（lncRNA），可稳定KMT2E蛋白，增加表观遗传组蛋白H3的4号位赖氨酸三甲基化（H3K4me3），驱动依赖HIF-2α的代谢和致病性内皮活性。该lncRNA信号通路还增加了表观遗传、转录和转录后环境中的HIF-2α表达，从而形成正反馈，进一步增强HIF-2α活性。在本研究中，作者在PAH患者队列以及全球荟萃分析中确定了KMT2E内含子内的一个单核苷酸变异（SNV）rs73184087与PAH疾病的遗传风险相关。该SNV特定的等位基因与HIF-2α形成关联，参与长程染色质相互作用，并在缺氧细胞中诱导KMT2E-AS1和KMT2E的相互作用。体内实验中，KMT2E-AS1缺失可以保护小鼠免受PAH侵害，通过药物抑制大鼠组蛋白甲基化也有相同作用。而与之对应的，强制这一lncRNA表达会形成更严重的疾病表现。因此，KMT2E-AS1/KMT2E介导HIF-2α病理，是肺动脉高压的关键临床靶点。▲KMT2E-AS1诱导HIF-2α激活并阻止HIF-2α降解，从而驱动内皮病理表型（图片来源：参考资料[3]）潜在靶点众多，限于篇幅，本文不一一进行介绍。请点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Chen, Yun et al. “APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread.” Cell vol. 187,2 (2024): 428-445.e20. doi:10.1016/j.cell.2023.11.029[2] Sreekumar, Amulya et al. “B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.” Cancer cell vol. 42,1 (2024): 52-69.e7. doi:10.1016/j.ccell.2023.11.008[3] Tai, Yi-Yin et al. “Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.” Science translational medicine vol. 16,729 (2024): eadd2029. doi:10.1126/scitranslmed.add2029免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新