搜索将覆盖在初级淋巴结上孵化的新基因
Re­search­ers dis­cover a novel gene in­volved in primary lymph­ed­ema

Re­search­ers dis­cover a novel gene in­volved in primary lymph­ed­ema

搜索将覆盖在初级淋巴结上孵化的新基因

ANGPT2媒介TIE2和TIE1在原子分辨率下集群和激活的新模式。信贷: VM Leppanen等人, Sci .Transl .Med .12 , eaax8013(2020)

日前(世贸组织)由Miikka Vikkula教授领导的de Duve研究所人类分子遗传学实验室(UCLouvain)确定了新基因ANGPT2中的突变,该基因负责初级淋巴细胞。这些实验室与Wihuri研究所及其所长赫尔辛基大学卡里·阿利塔洛教授一道,可以表明这些突变是如何造成这种疾病的。

"突变导致ANGPT2蛋白质的正常功能丧失,众所周知, ANGPT2蛋白质在淋巴和血管成熟中起着作用。Alitalo教授解释说,这一重要发现为发展更好的淋巴治疗提供了可能性。

该发现是发表在《科学转化医学》上的日前 。

ANGPT2基因突变对人类首次表现出淋巴瘤的影响

淋巴细胞是由于淋巴细胞系统发育或功能异常而导致的一种严重的慢性疾病。在病人中,淋巴从组织中抽干得不好,因此在四肢累积,造成肿胀和纤维化,限制了受影响身体部分的活动能力,增加了感染的可能性。淋巴细胞可以是主要的,没有已知的根本原因,也可以是次要的,如果是切除或损坏的淋巴细胞造成的,例如手术、感染或癌症治疗。小学毕业生往往继承下来。

德杜夫研究所的小组及其庞大的国际合作者网络,包括布鲁塞尔Saint - Luc医院血管分析中心和医学遗传学中心,收集了近900名初级淋巴瘤患者的样本,并从其家人那里收集样本。通过使用全基因组测序(即基因组所有编码部分的测序),在5个家庭的淋巴细胞患者中发现了ANGPT2中的突变。

ANGPT2对血管皮锡2蛋白进行编码,这是一种生长因素,与Alitalo教授实验室首次发现的血液和淋巴细胞中的受体有关联。

阿利塔洛教授说: “ ANGPT2此前曾被证明会影响小鼠的淋巴细胞发育,但这是首次发现该基因中的突变会给人类带来淋巴细胞。 ”

关于导致体操的机制的新信息a

在确定的突变中,有一个摘除了整个基因的一个副本,而另外四个是氨基酸的替代。研究人员发现,其中三种变性剂没有从通常产生蛋白质的细胞中适当地分泌出来,这也减少了从剩余的正常细胞中产生的蛋白质的分泌性。因此,这些突变产生了所谓的支配性负面影响。第四种消化剂极积极地促使稀释的淋巴船增加扩散。这种变质显示了结合的变化。

导致患者出现初级淋巴瘤的突变使人们对ANGPT2蛋白质的功能和导致淋巴瘤的机制有了重要的了解。

查明对更好地管理这一疾病至关重要的遗传原因

在欧洲,有100多万人受到淋巴的影响。治疗仅限于反复手工按摩和使用旨在减少组织肿胀的压抑服装。在某些情况下,手术可能是有益的。另一个淋巴细胞生长因子VEGF - C目前正在进行临床试验,同时对因乳腺癌转移而切除手臂淋巴结的病人进行淋巴细胞治疗手术。到目前为止,淋巴细胞还没有治愈办法,只有在少数情况下随着时间的推移才会得到解决或改善。

"查明遗传原因对于更好地管理这一疾病至关重要。这使更准确和更可靠的诊断成为可能,今天,许多患者仍未得到诊断。正如新发表的研究报告所显示的那样,淋巴细胞的研究有助于深入了解潜在的细胞机制,而这些机制可能是开发新疗法的目标, ”阿利塔洛教授说。

The Human Molecular Genetics laboratory of the de Duve Institute (UCLouvain), headed by Professor Miikka Vikkula, recently identified mutations in a novel gene, ANGPT2, responsible for primary lymphedema. Together with the Wihuri Research Institute and its director, Professor Kari Alitalo at the University of Helsinki, the laboratories could show how these mutations cause the disease.

"The mutations result in loss of the normal function of the ANGPT2 protein that is known to play a role in lymphatic and blood vessel maturation. This important discovery opens possibilities for the development of improved treatments of lymphedema," explains Professor Alitalo.

The discovery is recently published in Science Translational Medicine.

Influence of the ANGPT2 gene mutations causing lymphedema shown in humans for the first time

Lymphedema is a strongly invalidating chronic disease resulting from abnormal development or function of the lymphatic system. In the patients, lymph is poorly drained from tissues, and thus accumulates in the extremities, causing swelling and fibrosis, limiting the mobility of the affected body part and increasing the likelihood of infections. Lymphedema can be either primary, which has no known underlying cause, or secondary, when it results from removed or damaged lymph vessels, e.g., after surgery, infection or cancer treatment. Primary lymphedema is often inherited.

The team of the de Duve Institute with its large international network of collaborators, including the Center for Vascular Anomalies and the Center for Medical Genetics of the Saint-Luc hospital in Brussels, has collected samples from almost 900 patients suffering from primary lymphedema, also collecting samples from their family members. By using whole-exome sequencing (i.e., the sequencing of all the coding parts of the genes in the genome), mutations in ANGPT2 were discovered in lymphedema patients from five families.

The ANGPT2 encodes the angiopoietin 2 protein, a growth factor that binds to receptors in blood and lymphatic vessels that were first identified in Professor Alitalo's laboratory.

"ANGPT2 has previously been shown to influence lymphatic development in mice, but this is the first time when mutations in this gene were found to cause lymphedema in humans," says Professor Alitalo.

New information on mechanisms that lead to lymphedema

Among the identified mutations, one deletes one copy of the entire gene, whereas the four others are amino acid substitutions. The researchers showed that three of the mutants are not properly secreted from cells that normally produce the protein, and this also decreases the secretion of the protein produced from the remaining normal allele. Thus, the mutations had a so called dominant-negative effect. The fourth mutant was hyperactive in inducing increased proliferation of dilated lymphatic vessels. This mutant demonstrated altered integrin binding.

The mutations that resulted in primary lymphedema in patients provided important insights into the function of the ANGPT2 protein and mechanisms that lead to lymphedema.

Identifying the genetic causes crucial for a better management of the disease

In Europe, over 1 million people are affected by lymphedema. Therapy is limited to repeated manual lymphatic massage and use of compressive garments intended to decrease tissue swelling. In some cases, surgery may be helpful. Another lymphatic vessel growth factor, VEGF-C, is currently undergoing clinical trial in combination with surgery for the treatment of lymphedema in patients whose lymph nodes in the armpit have been removed due to breast cancer metastasis. So far, no cure exists for lymphedema and it resolves or ameliorates with time only in a minority of cases.

"Identifying the genetic causes is crucial for a better management of the disease. It makes a more precise and reliable diagnosis possible, where today, many people with the disease are still not diagnosed. As the newly published study shows, research on lymphedema leads to insight in the underlying cellular mechanisms, which may be targets for the development of new therapies," Professor Alitalo says.

A new model of ANGPT2-mediated TIE2 and TIE1 clustering and activation at atomic resolution. Credit: VM Leppanen et al., Sci. Transl. Med. 12, eaax8013 (2020)

ANGPT2媒介TIE2和TIE1在原子分辨率下集群和激活的新模式。信贷: VM Leppanen等人, Sci .Transl .Med .12 , eaax8013(2020)

The Human Molecular Genetics laboratory of the de Duve Institute (UCLouvain), headed by Professor Miikka Vikkula, recently identified mutations in a novel gene, ANGPT2, responsible for primary lymphedema. Together with the Wihuri Research Institute and its director, Professor Kari Alitalo at the University of Helsinki, the laboratories could show how these mutations cause the disease.

日前(世贸组织)由Miikka Vikkula教授领导的de Duve研究所人类分子遗传学实验室(UCLouvain)确定了新基因ANGPT2中的突变,该基因负责初级淋巴细胞。这些实验室与Wihuri研究所及其所长赫尔辛基大学卡里·阿利塔洛教授一道,可以表明这些突变是如何造成这种疾病的。

"The mutations result in loss of the normal function of the ANGPT2 protein that is known to play a role in lymphatic and blood vessel maturation. This important discovery opens possibilities for the development of improved treatments of lymphedema," explains Professor Alitalo.

"突变导致ANGPT2蛋白质的正常功能丧失,众所周知, ANGPT2蛋白质在淋巴和血管成熟中起着作用。Alitalo教授解释说,这一重要发现为发展更好的淋巴治疗提供了可能性。

The discovery is recently published in Science Translational Medicine.

该发现是发表在《科学转化医学》上的日前 。

Influence of the ANGPT2 gene mutations causing lymphedema shown in humans for the first time

ANGPT2基因突变对人类首次表现出淋巴瘤的影响

Lymphedema is a strongly invalidating chronic disease resulting from abnormal development or function of the lymphatic system. In the patients, lymph is poorly drained from tissues, and thus accumulates in the extremities, causing swelling and fibrosis, limiting the mobility of the affected body part and increasing the likelihood of infections. Lymphedema can be either primary, which has no known underlying cause, or secondary, when it results from removed or damaged lymph vessels, e.g., after surgery, infection or cancer treatment. Primary lymphedema is often inherited.

淋巴细胞是由于淋巴细胞系统发育或功能异常而导致的一种严重的慢性疾病。在病人中,淋巴从组织中抽干得不好,因此在四肢累积,造成肿胀和纤维化,限制了受影响身体部分的活动能力,增加了感染的可能性。淋巴细胞可以是主要的,没有已知的根本原因,也可以是次要的,如果是切除或损坏的淋巴细胞造成的,例如手术、感染或癌症治疗。小学毕业生往往继承下来。

The team of the de Duve Institute with its large international network of collaborators, including the Center for Vascular Anomalies and the Center for Medical Genetics of the Saint-Luc hospital in Brussels, has collected samples from almost 900 patients suffering from primary lymphedema, also collecting samples from their family members. By using whole-exome sequencing (i.e., the sequencing of all the coding parts of the genes in the genome), mutations in ANGPT2 were discovered in lymphedema patients from five families.

德杜夫研究所的小组及其庞大的国际合作者网络,包括布鲁塞尔Saint - Luc医院血管分析中心和医学遗传学中心,收集了近900名初级淋巴瘤患者的样本,并从其家人那里收集样本。通过使用全基因组测序(即基因组所有编码部分的测序),在5个家庭的淋巴细胞患者中发现了ANGPT2中的突变。

The ANGPT2 encodes the angiopoietin 2 protein, a growth factor that binds to receptors in blood and lymphatic vessels that were first identified in Professor Alitalo's laboratory.

ANGPT2对血管皮锡2蛋白进行编码,这是一种生长因素,与Alitalo教授实验室首次发现的血液和淋巴细胞中的受体有关联。

"ANGPT2 has previously been shown to influence lymphatic development in mice, but this is the first time when mutations in this gene were found to cause lymphedema in humans," says Professor Alitalo.

阿利塔洛教授说: “ ANGPT2此前曾被证明会影响小鼠的淋巴细胞发育,但这是首次发现该基因中的突变会给人类带来淋巴细胞。 ”

New information on mechanisms that lead to lymphedema

关于导致体操的机制的新信息a

Among the identified mutations, one deletes one copy of the entire gene, whereas the four others are amino acid substitutions. The researchers showed that three of the mutants are not properly secreted from cells that normally produce the protein, and this also decreases the secretion of the protein produced from the remaining normal allele. Thus, the mutations had a so called dominant-negative effect. The fourth mutant was hyperactive in inducing increased proliferation of dilated lymphatic vessels. This mutant demonstrated altered integrin binding.

在确定的突变中,有一个摘除了整个基因的一个副本,而另外四个是氨基酸的替代。研究人员发现,其中三种变性剂没有从通常产生蛋白质的细胞中适当地分泌出来,这也减少了从剩余的正常细胞中产生的蛋白质的分泌性。因此,这些突变产生了所谓的支配性负面影响。第四种消化剂极积极地促使稀释的淋巴船增加扩散。这种变质显示了结合的变化。

The mutations that resulted in primary lymphedema in patients provided important insights into the function of the ANGPT2 protein and mechanisms that lead to lymphedema.

导致患者出现初级淋巴瘤的突变使人们对ANGPT2蛋白质的功能和导致淋巴瘤的机制有了重要的了解。

Identifying the genetic causes crucial for a better management of the disease

查明对更好地管理这一疾病至关重要的遗传原因

In Europe, over 1 million people are affected by lymphedema. Therapy is limited to repeated manual lymphatic massage and use of compressive garments intended to decrease tissue swelling. In some cases, surgery may be helpful. Another lymphatic vessel growth factor, VEGF-C, is currently undergoing clinical trial in combination with surgery for the treatment of lymphedema in patients whose lymph nodes in the armpit have been removed due to breast cancer metastasis. So far, no cure exists for lymphedema and it resolves or ameliorates with time only in a minority of cases.

在欧洲,有100多万人受到淋巴的影响。治疗仅限于反复手工按摩和使用旨在减少组织肿胀的压抑服装。在某些情况下,手术可能是有益的。另一个淋巴细胞生长因子VEGF - C目前正在进行临床试验,同时对因乳腺癌转移而切除手臂淋巴结的病人进行淋巴细胞治疗手术。到目前为止,淋巴细胞还没有治愈办法,只有在少数情况下随着时间的推移才会得到解决或改善。

"Identifying the genetic causes is crucial for a better management of the disease. It makes a more precise and reliable diagnosis possible, where today, many people with the disease are still not diagnosed. As the newly published study shows, research on lymphedema leads to insight in the underlying cellular mechanisms, which may be targets for the development of new therapies," Professor Alitalo says.

"查明遗传原因对于更好地管理这一疾病至关重要。这使更准确和更可靠的诊断成为可能,今天,许多患者仍未得到诊断。正如新发表的研究报告所显示的那样,淋巴细胞的研究有助于深入了解潜在的细胞机制,而这些机制可能是开发新疗法的目标, ”阿利塔洛教授说。