更新于：2024-05-01

AMER1

APC membrane recruitment protein 1

更新于：2024-05-01

基本信息

别名

AMER1、APC membrane recruitment protein 1、FAM123B

+ [5]

简介

Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.

关联

100 项与 AMER1 相关的临床结果

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100 项与 AMER1 相关的转化医学

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0 项与 AMER1 相关的专利（医药）

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166

项与 AMER1 相关的文献（医药）

2024-02-02·Medicine

Whole-exome sequencing of pathogenic genes in a family with congenital heart disease: A case report.

Article

作者: Li Chang ; Renhui Ji ; Rina Sa ; Jiletu Huge ; Caiyan An

RATIONALE:

Congenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease.

PATIENT CONCERNS AND DIAGNOSES:

Three generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease.

OUTCOMES:

The first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.

2024-01-05·International journal of molecular sciences

amer1 Regulates Zebrafish Craniofacial Development by Interacting with the Wnt/β-Catenin Pathway.

Article

作者: Le Sun ; Lu Ping ; Xinmiao Fan ; Yue Fan ; Bo Zhang ; Xiaowei Chen

Microtia-atresia is a rare type of congenital craniofacial malformation causing severe damage to the appearance and hearing ability of affected individuals. The genetic factors associated with microtia-atresia have not yet been determined. The AMER1 gene has been identified as potentially pathogenic for microtia-atresia in two twin families. An amer1 mosaic knockdown zebrafish model was constructed using CRISPR/Cas9. The phenotype and the development process of cranial neural crest cells of the knockdown zebrafish were examined. Components of the Wnt/β-catenin pathway were examined by qPCR, Western blotting, and immunofluorescence assay. IWR-1-endo, a reversible inhibitor of the Wnt/β-catenin pathway, was applied to rescue the abnormal phenotype. The present study showed that the development of mandibular cartilage in zebrafish was severely compromised by amer1 knockdown using CRISPR/Cas9. Specifically, amer1 knockdown was found to affect the proliferation and apoptosis of cranial neural crest cells, as well as their differentiation to chondrocytes. Mechanistically, amer1 exerted an antagonistic effect on the Wnt/β-catenin pathway. The application of IWR-1-endo could partially rescue the abnormal phenotype. We demonstrated that amer1 was essential for the craniofacial development of zebrafish by interacting with the Wnt/β-catenin pathway. These findings provide important insight into the role of amer1 in zebrafish mandibular development and the pathology of microtia-atresia caused by AMER1 gene mutations in humans.

2024-01-04·The Journal of clinical endocrinology and metabolism

A mosaic variant in CTNNB1/β-catenin as a novel cause for osteopathia striata with cranial sclerosis.

Article

作者: Yentl Huybrechts ; Natasha M Appelman-Dijkstra ; Ellen Steenackers ; Wouter Van Beylen ; Geert Mortier ; Gretl Hendrickx ; Wim Van Hul

CONTEXT:

Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of β-catenin via AXIN stabilization, acting as a negative regulator of the WNT/β-catenin signaling pathway, a central pathway in bone formation.

RESULTS:

In this study, we describe a Dutch adult woman with an OSCS-like phenotype, i.e. generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1. Whole exome sequencing led to the identification of a mosaic missense variant (c.876A>C; p.Lys292Asn) in CTNNB1, coding for β-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the β-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the β-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn β-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn β-catenin.

CONCLUSION:

In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.

项与 AMER1 相关的新闻（医药）

2023-05-09

·生物谷

Gastroenterology：复旦大学徐烨/胡欣团队绘制中国人结直肠癌基因变异图谱，助力优化靶向和免疫治疗方案

研究结果表明，BRAF和RBM10单基因驱动突变是转移性结直肠癌较短无进展生存期的独立预后因素，且体外实验表明RBM10表达缺失促进肿瘤细胞增殖、迁移并抑制凋亡。结直肠癌是严重威胁我国居民生命健康的恶性疾病。随着居民生活方式的变化和健康筛查意识的提升，我国结直肠癌发病人数越来越多。然而，高化疗耐受和高复发转移率仍是阻碍结直肠癌患者获得长期生存的瓶颈，约20-25%的患者在初诊时即伴随转移，另有30%的I-III期和65%的IV期患者出现复发或二次转移。由于结直肠癌复杂的分子发病机制，致使其具有高度的肿瘤异质性。因此，寻找结直肠癌个体化肿瘤靶标，探索结直肠癌的精准治疗，对于打破结直肠癌治疗‘瓶颈’具有重要临床转化价值。目前，以分子免疫治疗、靶向治疗等治疗方式为代表的精准策略已经在结直肠癌研究领域广泛开展。然而，当前相关治疗标准和治疗指南绝大多数参考人群为西方群体，基于中国人群的结直肠癌基因组变异特征图谱仍然处于“空白”状态。近日，复旦大学附属肿瘤医院徐烨教授团队与胡欣教授合作，在国际权威学术期刊 Gastroenterology 上发表了题为：Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Colorectal Cancer Prognosis 的研究论文。该研究成功绘制出迄今国内最大规模的结直肠癌基因组变异图谱，揭示了中国人群结直肠癌基因组变异特征，并鉴定出其中可精准预测结直肠癌靶向治疗和免疫治疗疗效的基因组标志物，为结直肠癌的基础临床转化拓宽了思路。该研究基于中国人群结直肠肿瘤的前瞻性队列，纳入了869例结直肠癌患者，其中包括586例早期和283例晚期结直肠癌。利用887基因Panel测序，绘制体系和胚系变异图谱，描述了中国人群结直肠癌临床病理和基因组变异特征。这也是迄今国内最大规模的结直肠癌前瞻性靶向测序平台和临床样本队列。基因图谱显示，在结直肠癌体系变异方面，突变频率前三位分别为TP53（72%）、APC（63%）和KRAS（42%），癌症信号通路突变图谱与高加索人群相比差异较大，呈现出中国结直肠癌患者群体的独有特征。在胚系变异方面，4.6%的患者携带DNA损伤修复通路相关的明确致病或可能致病性胚系突变，其中27.5%易感基因携带者发生因杂合性缺失或双等位基因变异导致的“二次打击”事件。此外，研究结果表明，BRAF和RBM10单基因驱动突变是转移性结直肠癌较短无进展生存期的独立预后因素，且体外实验表明RBM10表达缺失促进肿瘤细胞增殖、迁移并抑制凋亡。胡欣教授表示，这可能是导致结直肠癌复发转移的诱因之一。基因组变异互作网络分析共获得65个共现和106个互斥潜在功能依赖性事件，其中KRAS/AMER1和KRAS/APC共现突变可加速药物代谢，导致对以化疗为基石的治疗敏感性较差，从而使得患者在进行化疗时临床获益有限。研究团队发现，联合基因组标志物可优化免疫治疗疗效预测，且这种预测在复旦大学肿瘤医院精准肿瘤中心的免疫检查点抑制剂治疗队列中得到验证。微卫星高度不稳定且插入缺失变异高负荷的肿瘤，在接受免疫治疗后完全退缩，展现‘热’免疫微环境特征，其高免疫原性肿瘤新抗原经MHC-II复合物递呈给CD4+ T细胞而激活细胞毒效应。相反，POLE功能性突变携带者接受免疫治疗后，疾病发生进展，尽管有极高的肿瘤突变负荷，但大量由非同义单核苷酸变异衍生新抗原的递呈功能缺陷并多发耗竭，伴随相对较少活化淋巴细胞浸润、免疫检查点表达及PD-1/PD-L1共定位等，整体呈现相对“冷”免疫表型。徐烨教授表示，这一发现提示我们可以据此优化预测免疫治疗疗效的基因组标志物，更精准识别获益人群，为广大结直肠癌患者的精准诊疗提供新希望。复旦大学附属肿瘤医院徐烨教授、胡欣教授加州大学洛杉矶分校 Zhang Liying 为论文共同通讯作者，复旦大学附属肿瘤医院国琳玮博士、王云锦博士和杨闻箫硕士为论文共同第一作者。