ACVR1B

ACVR1B (Activin A Receptor Type 1B) is a gene encoding a transmembrane serine/threonine kinase, which is essential for signaling within the transforming growth factor-beta (TGF-β) superfamily. 

Activins, dimeric growth and differentiation factors, signal through a complex of type I and type II receptor serine kinases, including ACVR1B. 

This receptor, upon activin binding to type II receptors (ACVR2A or ACVR2B), activates and phosphorylates SMAD2 and SMAD3 proteins. The phosphorylated SMAD proteins then form a complex that translocates to the nucleus, regulating gene expression involved in various physiological and pathological processes. 

ACVR1B is known to play significant roles in growth, development, and inflammation. It modulates cytokine secretion, induces nitric oxide production, and regulates immune cell activity. 

Mutations in ACVR1B have been implicated in various cancers, including pancreatic cancer, where it acts as a tumor suppressor gene. Its role extends to congenital heart defects like transposition of the great arteries (DTGA), where its mutations disrupt normal heart development signaling pathways. 

In sepsis, elevated ACVR1B expression in neutrophils exposed to septic plasma highlights its potential as a biomarker and therapeutic target. 

Furthermore, single nucleotide polymorphisms (SNPs) in ACVR1B, such as rs12809597, are associated with increased lung cancer risk, especially in non-smokers exposed to second-hand smoke, emphasizing its relevance in inflammatory and proliferative diseases.

What is ACVR1B? [1., 8.] 

The ACVR1B gene encodes an activin A type IB receptor, a transmembrane serine/threonine kinase that plays a crucial role in the transforming growth factor-beta (TGF-beta) superfamily signaling. [1.] 

Activins, which are dimeric growth and differentiation factors, signal through a complex of receptor serine kinases, including at least two type I and two type II receptors. ACVR1B is a type I receptor essential for this signaling process.

Upon activin’s binding to type II receptors (ACVR2A or ACVR2B), these receptors activate their serine-threonine kinase, which subsequently phosphorylates and activates the type I receptor ACVR1B. 

Once activated, ACVR1B phosphorylates SMAD2 and SMAD3 proteins. Various SMAD proteins are then involved in a process that includes dissociation from the receptor and formation of a new SMAD protein complex.

This SMAD complex then translocates into the nucleus, where it mediates activin-induced transcription, regulating numerous physiological and pathological processes.

The activin signal is also modulated by inhibitory SMAD7, which can be recruited to ACVR1B through FKBP1A, thereby preventing the association of SMAD2 and SMAD3 with the activin receptor complex and blocking the activin signal. 

Additionally, inhibin-B can antagonize activin signal transduction by binding to the receptor through the IGSF1 inhibin coreceptor. 

ACVR1B is also involved in phosphorylating TDP2 and in the NF-kappaB pathway, highlighting its broad role in cellular signaling and regulation, and inflammation and immune regulation.

ACVR1B plays a crucial role in regulating growth and development as a key component of the transforming growth factor-beta (TGF-β) superfamily signaling pathway. Its activation regulates various downstream physiological processes including embryonic development, follicle development, and cellular growth and differentiation. [1.] 

ACVR1B and the Inflammatory Response [4., 5.] 

ACVR1B, part of the TGF-beta superfamily, is involved in modulating the inflammatory response. This includes altering cytokine secretion, inducing nitric oxide production, and regulating immune cell activity. [4.] 

ACVR1B (Activin A Receptor Type 1B) is important in the NF-kappaB signaling pathway, which is vital for regulating immune responses, inflammation, and cell survival. 

The SMAD protein complex, which translocates to the nucleus to mediate transcription of target genes involved in various physiological and pathological processes, induces gene expression of proteins involved in immune regulation and inflammation. 

Inhibitory SMAD7 can block this signaling by preventing the association of SMAD2 and SMAD3 with the receptor complex, thereby modulating the pathway's activity. 

Mutations in ACVR1B are linked to various cancers, including pancreatic cancer, indicating its significant role in tumorigenesis and potential as a therapeutic target. [5.] 

ACVR1B in Health and Disease 

Pancreatic Cancer [7.]

ACVR1B has been identified as a tumor suppressor gene in pancreatic cancer, with somatic mutations found in this type of cancer.

Studies have shown that the loss of ACVR1B accelerates the development of pancreatic intraepithelial neoplasias (PanINs) and pancreatic intraductal papillary mucinous neoplasms (IPMNs), precursor lesions that can progress to invasive pancreatic cancer. [7.] 

The inactivation of ACVR1B in conjunction with other mutations, such as in the tumor-suppressor gene MADH4 (Smad4), leads to significant increases in pancreatic tumor burden and a decrease in survival rates. 

Transposition of the Great Arteries, Dextro-Looped [2.] 

Transposition of the great arteries, dextro-looped (DTGA), is a congenital heart defect where the aorta arises from the right ventricle and the pulmonary artery from the left ventricle, resulting in two separate circulatory systems that are incompatible with life without surgical intervention. 

Patients may have associated cardiac anomalies, such as atrial or ventricular septal defects, which allow some mixing of blood to sustain life temporarily. 

ACVR1B (Activin A Receptor Type 1B) has been implicated in DTGA, with mutations in this gene contributing to the condition. 

These mutations disrupt normal signaling pathways involved in heart development, necessitating early diagnosis and surgical correction for survival.

Sepsis and Inflammatory Conditions [4.] 

ACVR1B is crucial for activin signaling, which plays roles in cell proliferation, apoptosis, and immune response. This signaling involves the binding of activins to a receptor complex that includes ACVR1B, leading to the activation of SMAD proteins and subsequent regulation of gene expression.

One study found increased ACVR1B expression in neutrophils exposed to septic plasma and confirmed these findings using datasets from public repositories. Additionally, RT-qPCR analysis of buffy coat samples from healthy donors exposed to septic plasma showed a significant increase in ACVR1B transcripts. [4.] 

These findings suggest that ACVR1B might be a valuable marker for understanding the pathogenesis of sepsis and could offer insights into new therapeutic targets. 

The variability in response among different individuals indicates that genetic factors, such as SNPs in the ACVR1B gene, may influence expression levels and the immune response to sepsis.

Lung Cancer and Chronic Obstructive Pulmonary Disease (COPD)

Single nucleotide polymorphisms (SNPs) in the ACVR1B gene have been associated with an increased risk of lung cancer, particularly in relation to tobacco smoke exposure. [6.] 

Additionally, another study found potential implications for ACVR1B gene SNPs in chronic obstructive pulmonary disease (COPD). [3.] These observations suggest a link between ACVR1B genetic variations and susceptibility to lung-related inflammatory conditions, including cancer. 

This connection is part of the broader context in which ACVR1B is implicated in inflammatory and proliferative processes in various diseases. 

Big Picture: Cancer Processes 

As a member of the transforming growth factor-beta (TGF-beta) superfamily, ACVR1B is involved in various physiological processes including cell proliferation and apoptosis. 

ACVR1B gene mutations have been associated with cancer. [4.] The gene encodes a type I receptor essential for activin signaling, which plays a role in numerous cellular functions, including growth and differentiation. 

Mutations are linked to several types of cancer, suggesting that ACVR1B acts as a tumor suppressor gene. [4.] 

While specific types are not always mentioned, ACVR1B is frequently associated with various cancers in the literature, often in the context of its role in cell proliferation and as part of the TGF-beta superfamily signaling pathway.

Genetic Alterations in the ACVR1B Gene

The gene for the ACVR1B protein may contain alterations or mutations that cause increase or decrease of function of the ACVR1B protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in Function of ACVR1B

rs12809597 [6.] 

The SNP rs12809597 in the ACVR1B gene was found to be associated with lung cancer risk in lifetime never smokers exposed to second-hand smoke.

This SNP is intronic and does not have a reported function. It is likely a tagSNP linked to other causal SNPs affecting the expression or function of ACVR1B.

rs2701129 [6.] 

While not directly in ACVR1B, this SNP in the nearby NR4A1 gene was found to be potentially relevant when investigating ACVR1B-related lung cancer risk.

rs1882119 [6.] 

An imputed SNP in the NR4A1 gene that showed a strong association when investigating the region around ACVR1B for lung cancer risk.

Laboratory Testing for ACVR1B

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

FAQ: ACVR1B (Activin A Receptor Type 1B)

What is ACVR1B?

ACVR1B (Activin A Receptor Type 1B) is a gene that encodes a protein known as activin receptor type-1B. 

This receptor is involved in the signaling pathways of the transforming growth factor-beta (TGF-β) superfamily, which regulate various cellular processes, including growth, differentiation, apoptosis, and homeostasis.

What is the Function of ACVR1B in the Body?

ACVR1B plays a crucial role in:

• Cell signaling: Mediating the effects of activins and other TGF-β family members on cellular functions.

• Regulation of growth and development: Involved in processes such as embryogenesis, tissue development, and cellular differentiation.

• Homeostasis and repair: Participating in the maintenance and repair of tissues.

What are the Implications of Mutations in the ACVR1B Gene?

Mutations in the ACVR1B gene can lead to several health issues, including:

• Cancer: Abnormal ACVR1B signaling has been implicated in the development and progression of various cancers, such as pancreatic and colorectal cancers.

• Developmental disorders: Mutations may also affect normal development and lead to congenital anomalies such as Transposition of the Great Arteries, Dextro-Looped.

How are ACVR1B-Related Conditions Diagnosed?

Conditions related to ACVR1B mutations can be diagnosed through genetic testing to identify mutations in the ACVR1B gene.

What are the Health Implications of ACVR1B Mutations?

ACVR1B mutations can lead to various health issues, such as:

• Cancer progression: Altered signaling pathways can promote tumor growth and metastasis.

• Developmental abnormalities: Disruptions in normal signaling can cause congenital defects and developmental disorders such as Transposition of the Great Arteries, Dextro-Looped. 

How are ACVR1B-Related Conditions Managed?

Management of conditions related to ACVR1B mutations involves:

• Targeted therapies: Developing and using treatments that specifically target abnormal ACVR1B signaling pathways in cancers.

• Symptom management: Treating the symptoms and complications arising from developmental disorders or congenital anomalies.

• Regular monitoring: Ongoing medical surveillance to manage and mitigate the impact of ACVR1B-related conditions.

Are There Lifestyle Changes That Can Support the Management of ACVR1B-Related Conditions?

While lifestyle changes cannot directly affect the genetic basis of ACVR1B-related conditions, maintaining overall health can support management:

• Healthy diet: Consuming a balanced diet rich in nutrients to support overall health.

• Regular exercise: Engaging in physical activity to maintain physical and mental well-being.

• Avoiding known carcinogens: Reducing exposure to substances that can increase cancer risk, such as tobacco and excessive alcohol.

Where Can I Find More Information About ACVR1B and Related Conditions?

For more information about ACVR1B and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on ACVR1B and its role in health and disease.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and the American Cancer Society (ACS).

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