更新于：2024-11-01

ALMS1

更新于：2024-11-01

基本信息

别名

ALMS1、ALMS1 centrosome and basal body associated protein、Alstrom syndrome protein 1

+ [2]

简介

Involved in PCM1-dependent intracellular transport. Required, directly or indirectly, for the localization of NCAPD2 to the proximal ends of centrioles. Required for proper formation and/or maintenance of primary cilia (PC), microtubule-based structures that protrude from the surface of epithelial cells.

关联

项与 ALMS1 相关的药物

PATAS

靶点

ALMS1 x PKCα

作用机制

ALMS1调节剂 [+1]

在研机构

Institut de Genetique et de Biologie Moleculaire et Cellulaire [+2]

原研机构

AdipoPharma SAS

在研适应症

纤维化 [+4]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ALMS1 相关的临床结果

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100 项与 ALMS1 相关的转化医学

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0 项与 ALMS1 相关的专利（医药）

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256

项与 ALMS1 相关的文献（医药）

2025-01-01·Gene

Chromoanagenesis of chromosome 22 in a subject with obesity and borderline cognitive performance

Article

作者: Mio, Catia ; De Paoli, Federica ; Baldan, Federica ; Limongelli, Ivan ; Damante, Giuseppe ; Faletra, Flavio ; Morgan, Anna ; Passon, Nadia ; Gnan, Chiara ; Allegri, Lorenzo ; Demori, Eliana ; Zucca, Susanna ; Girotto, Giorgia

Chromoanagenesis events consist of complex chromosome rearrangements with multiple breakpoints in one or few chromosomes. Mechanisms of chromoanagenesis are split into three major groups: chromothripsis, chromoanasynthesis and chromoplexy. This study aims to delineate a chromoanagenesis event at the level of chromosome 22 in an individual showing obesity and borderline cognitive performance as major disturbances. The proband and his parents were subjected to conventional karyotyping, CGH array and whole genomic sequencing (WGS). By conventional karyotyping a "de novo" pericentric inversion of chromosome 22 was identified. CGH array identified several imbalances (either deletions or duplications) in the long arm of chromosome 22; the largest is a 4.5 Mb duplication at 22q12.1-22q1.3. The detection of extensive duplications would suggest the occurrence of a chromoanasynthesis event. WGS, in addition to the structural alterations identified by karyotyping and CGH array, revealed two translocations from chromosome 22 to chromosomes 6 and 21 as well as a heterozygous pathogenetic variant of ALMS1 gene; the latter could have contributed to the obesity of our patient. The pericentric inversion induces loss of initial part of TCF20 gene including the 5' regulatory region and the first, noncoding, exon. Heterozygous loss-of-function mutations of TCF20 gene have been found in patients with autism spectrum disorder or intellectual disability, some of them presenting obesity. It is, therefore, possible that disruption of TCF20 gene structure would contribute to a fraction of the patient's phenotype.

2024-12-01·Gene

Identification of novel compound heterozygous variants of the ALMS1 gene in a child with Alström syndrome by whole genome sequencing

Article

作者: Li, Dejun ; Zhang, Xiaofei ; Yang, Ying ; Sa, Sha ; Wang, Ziju ; Xu, Haikun

BACKGROUNDAlström syndrome (ALMS), a rare recessively inherited ciliopathy caused by mutations in ALMS1, is characterized by retinal dystrophy, childhood obesity, sensorineural hearing loss, and type 2 diabetes mellitus. The majority of pathogenic variants in ALMS1 are nonsense and frameshift mutations, which would lead to premature protein truncation, whereas copy number variants are seldom reported.METHODSHerein, we present a 10-year-old Chinese girl with ALMS. The potential causative genetic variant was confirmed through whole genome sequencing, quantitative real-time PCR analysis, and Sanger sequencing. Additionally, breakpoint analysis was performed to determine the exact breakpoint site of the large deletion and elucidate its probable formation mechanism.RESULTSThe patient had a cor triatriatum sinister (CTS) structure. Genetic analysis identified novel compound heterozygous variants in the patient, consisting of a frameshift variant c.4414_4415delGT (p.V1472Nfs*26) in ALMS1 and a novel large deletion at chr2:73,612,355-73,626,339, which encompasses exon 1 of the ALMS1 gene. Moreover, breakpoint analysis revealed that the large deletion probably formed through the microhomology-mediated end joining (MMEJ) mechanism due to the 6-bp microhomologies (TCCTTC) observed at both ends of the breakpoints.CONCLUSIONSIn this study, novel compound heterozygous variants in the ALMS1 gene were identified in an ALMS patient with a CTS structure. The molecular confirmation of these variants expands the mutational spectrum of ALMS1, while the manifestation of ALMS in the patient provides additional clinical insights into this syndrome.

2024-09-10·Animals : an open access journal from MDPI

Prevalence of Hypertrophic Cardiomyopathy and ALMS1 Variant in Sphynx Cats in New Zealand.

Article

作者: Munday, John S ; Connolly, David J ; Luis Fuentes, Virginia ; Loh, Yvonne ; Dutton, Emily ; Seo, Joonbum ; Hunt, Hayley

Recently, hypertrophic cardiomyopathy (HCM) in Sphynx cats has been associated with a variant in the gene encoding Alström syndrome protein 1 (ALMS1). The primary aims of this study were to describe the prevalence of HCM in Sphynx cats in New Zealand, and to assess the association between HCM and the ALMS1 variant in this population. In this prospective study, 55 apparently healthy Sphynx cats from registered Sphynx breeders and pet owners in New Zealand were screened by a cardiologist. A total of 42 of these cats had a repeat cardiac examination after median 1.8 years (range: 1.6-2.2). The frequency of the ALMS1 variant was 70.9% (11 homozygous and 28 heterozygous). At the median age of 5.8 years (range: 2.4-13.1), the prevalence of HCM was 40% (20 out of 55 cats). Three cats with HCM died during the study with congestive heart failure. All three cats had focal but extensive myocardial ischemia or infarction at necropsy. The ALMS1 variant was not associated with the HCM diagnosis. In summary, HCM was common in the studied cohort, suggesting Sphynx cats are predisposed to this disease. While the ALMS1 variant was also frequently detected, it was not associated with HCM in this population.

项与 ALMS1 相关的新闻（医药）

2022-07-15

·药明康德

▎药明康德内容团队编辑近日，内分泌代谢领域学术期刊Diabetes刊发了一项研究，科学家成功开发出一种新型肽分子PATAS，在小鼠模型中它有效逆转了可能引发2型糖尿病的代谢异常状况。作为常见的代谢异常病症，2型糖尿病（T2D）主要表现为血液中葡萄糖水平的异常升高，但它与1型糖尿病的发病机制有所不同。1型糖尿病是由于患者的免疫系统自我攻击导致胰腺细胞损伤，继而引发胰岛素分泌受阻，而T2D则是因机体的胰岛素抵抗所造成的。由于肥胖和人口老龄化，T2D的发病率逐年攀升，法国国家健康与医学研究院（Inserm）指出，“十多年来，仍然没有任何颠覆性的T2D疗法进入市场。”肥胖与胰岛素抵抗有着密切联系。脂肪细胞是机体代谢健康的重要调控因子，它们参与调控了机体胰岛素敏感性。肥大性脂肪细胞会出现糖摄取异常并导致胰岛素抵抗，这种现象存在于Alstrom综合征患者中（一种由于ALMS1基因突变所导致的单基因遗传病）。图片来源：123RF早期研究表明，由ALMS1蛋白功能失调所引起的脂肪组织异常在患有早发型T2D的Alstrom综合征患者中会引起严重的胰岛素抵抗。当研究人员将研究关注点转向ALMS1以及它和其他脂肪细胞蛋白的关系时，发现在没有胰岛素的情况下，ALMS1与脂肪细胞中的PKCα蛋白结合；胰岛素刺激会导致ALMS1和PKCα分离并将PKCα的相关功能结构域释放出来，从而使得葡萄糖进入细胞。然而在患有胰岛素抵抗的T2D人群中，两种蛋白质之间的结合得以维持，这造成了细胞糖摄取能力的降低。据此，研究人员围绕在ALMS1-PKCα结合状态下被抑制的功能结构域序列展开了筛选工作，并成功鉴定出可修复脂肪细胞糖摄取能力的肽段序列，研究人员将其命名为“PATAS”，它可以改善啮齿动物模型的全身性胰岛素抵抗、糖耐受不良、空腹血糖、肝脏脂肪变性和纤维化等多个代谢状况。在文中，作者写道：“在生物体内，PATAS降低了啮齿动物的全身胰岛素抵抗程度，并改善了葡萄糖耐受不良、空腹血糖、肝脏脂肪变性和纤维化等状况，故而PATAS代表了一种全新的‘first-in-class’肽类药物，它通过靶向脂肪细胞来改善胰岛素抵抗及其相关的合并症。”下一步研究计划是开展评估PATAS疗效的临床试验，在新闻稿中，研究人员表示这种药物不仅可以治疗T2D，还可以治疗同样有着脂肪细胞功能障碍和胰岛素抵抗症状的心脏代谢疾病。参考资料：[1] Edwige Schreyer, Cathy Obringer, et al; PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo. Diabetes 2022; db220058. https://doi.org/10.2337/db22-0058[2] Novel Peptide Could Create Pathway Against Insulin Resistance in Type 2 Diabetes, Retrieved July 14th, 2022, from https://www.biospace.com/article/new-peptide-could-create-pathway-against-insulin-resistance-in-type-2-diabetes-/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

免疫疗法First in Class

2022-07-13

·BioSpace

Novel Peptide Could Create Pathway Against Insulin Resistance in Type 2 Diabetes

A multinational research collaboration has developed a new peptide dubbed “PATAS”, which appears to fix the metabolic abnormalities leading to type 2 diabetes (T2D). The research was coordinated by Vincent Marion, Ph.D., with France-based Inserm in collaboration with the University of Birmingham (UK), Monash University (Australia) and with Dr. Alexander Fleming, M.D., former senior endocrinologist at the U.S. Food and Drug Administration, and was published Wednesday in the journal Diabetes. Type 2 diabetes is marked by high glucose levels in the blood. Unlike type 1 diabetes, which is an autoimmune disease caused by the patient’s immune system attacking and destroying the pancreas cells that produce insulin, type 2 diabetes is the result of insulin resistance in cells in the body. The incidence of T2D has been increasing for decades because of the obesity epidemic and an aging population. Inserm notes that there “have been no disruptive therapeutic innovations to reach market in over a decade.” Obesity is connected to hypertrophic adipocytes (oversized fat cells), which leads to impaired glucose absorption. Adipocytes are key regulators of whole-body metabolic fitness because of how they control insulin sensitivity. The new research, conducted on animal models, demonstrated that PATAS (peptide derived from PKC alpha Targeting AlmS) restored glucose uptake in the fat cells (adipocytes), which treated insulin resistance while benefiting the entire body. Earlier research suggested that adipose tissue abnormalities caused by a dysfunctional protein, ALMS1, led to severe insulin resistance in people with Alstrom syndrome who had early-onset T2D. In animal models, fixing this protein within the adipocytes restored blood glucose balance. Alstrom syndrome is a rare disease that affects many systems throughout the body. It includes obesity, T2D, short stature, heart disease and a progressive loss of vision and hearing. It is caused by mutations in the ALMS1 gene. The researchers then turned their focus on ALMS1 and how it relates to other adipocyte proteins. They found that in the absence of insulin, ALMS1 binds to a protein dubbed PKC alpha. Insulin activation caused ALMS1 and PKC alpha to separate, allowing glucose to enter cells. But in people with T2D insulin resistance, the connection between the two proteins is maintained. “Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolize it in order to synthesize and secrete lipids which are beneficial to the entire body. These positive effects are visible in our animal models, with a marked improvement in insulin resistance. Other parameters and comorbidities are also improved, including better blood glucose control and decreased liver fibrosis and steatosis,” Marion stated. The next step is a clinical trial to evaluate PATAS in humans. The researchers say this class of antidiabetic drugs may be able to treat not only T2D but also other cardio-metabolic diseases where dysfunctional adipocytes and insulin resistance are a problem. The authors wrote, “In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.” Currently, the most common treatments for T2D aside from weight loss and diet are glucagon-like peptide-1 (GLP-1) agonists, such as Eli Lilly’s Trulicity (dulaglutide), Novo Nordisk’s Victoza (liraglutide) and Ozempic (semaglutide).

First in Class

2022-06-17

·新浪医药新闻

FDA批准罕见肥胖症新药Imcivree治疗BBS患者

近日，美国FDA批准Rhythm制药公司药物Imcivree（setmelanotide）新适应症，用于治疗Bardet-Biedl综合征（BBS）患者，进行体重管理。 BBS是一种罕见的遗传病，症状广泛，包括严重肥胖。在美国，BBS影响约1500-2500人。BBS患者会经历无法满足的饥饿（贪食症），并在生命的早期就开始严重肥胖。其他症状包括视网膜变性、肾功能下降、手指或脚趾过多（多指）、性腺功能减退、学习障碍。 Imcivree最初于2021年获得FDA批准，用于治疗POMC、PCSK1或LEPR缺陷型肥胖症，这也是一类罕见的肥胖症，患者表现出无法满足的饥饿（贪食症）和早发严重肥胖。POMC、PCSK1或LEPR基因缺陷会损害黑皮质素4（MC4）受体通路。 Imcivree是第一款靶向MC4R通路损伤的治疗方法。MC4R在调节饥饿、热量摄入和能量消耗的生物学通路中起着关键作用。MC4R通路损伤也是与BBS相关的早发严重肥胖和贪食症的根本原因。3期临床试验数据显示，在无饮食控制和运动的情况下，接受Imcivree治疗的患者，第52周体重和饥饿感表现出统计学意义的显著降低：体重平均减轻7.9%，饥饿评分降低2.1分。除了批准Imcivree治疗BBS，FDA还针对Imcivree治疗Alstrom综合征的新适应症申请发布了一封完整回应函（CRL）。Alström综合征也是一种罕见的疾病，该病由ALMS1基因突变引起，影响多个系统和器官，疾病严重程度差别很差，特征包括肥胖、视力和听力损害、心肌病、2型糖尿病、身材矮小等。参考来源：Rhythm's Imcivree Scores FDA Approval in Bardet-Biedl Syndrome 内容来源于网络，如有侵权，请联系删除，谢谢