ACTB

The ACTB gene encodes the β-actin protein, a crucial component of the cytoskeleton involved in cell motility, structure, integrity, and intercellular signaling. 

β-actin, one of six highly conserved actin proteins, exists in monomeric (G-actin) and polymeric (F-actin) forms, essential for processes like cell migration and contraction. 

Mutations in ACTB can lead to developmental disorders such as Baraitser-Winter Syndrome 1 (BWS) and Dystonia-Deafness Syndrome 1 (DDS1), characterized by intellectual disability, distinctive facial features, and sensorineural deafness. 

Recent research also highlights ACTB's significant role in cancer, where its up-regulation in various tumors contributes to invasiveness and metastasis. 

Understanding ACTB's functions and mutations provides insights into its impact on health and disease, offering potential therapeutic targets.

What is ACTB? [1., 6.]

The ACTB gene encodes the β-actin protein, one of six different highly conserved actin proteins integral to cellular functions such as motility, structure, integrity, and intercellular signaling.  [1.] 

β-actin, a major component of the contractile apparatus and one of the two nonmuscle cytoskeletal actins, is ubiquitously expressed in all cells. The protein exists in monomeric (G-actin) and polymeric (F-actin) forms, both of which are crucial for processes like cell motility and contraction. 

Additionally, actin plays a role in the nucleus, regulating gene transcription and DNA repair.

Mutations in ACTB can lead to Baraitser-Winter Syndrome 1, characterized by intellectual disability and distinctive facial features, as well as Dystonia-Deafness Syndrome 1. [1.] 

This gene is also associated with pathways related to actin dynamics and phagocytic cup formation, which is the cellular ingestion of large particles (>0.5 μm) such as bacteria, dead cells, or other foreign materials.

Numerous pseudogenes of ACTB are scattered throughout the human genome.

Editing the ACTB gene to express γ-actin instead of β-actin, while preserving its regulatory sequences, induced progressive hearing loss due to the degeneration of auditory sensory cells (stereocilia) in mice. [6.] 

This highlights that β-actin’s unique functions are driven by its nucleotide sequence and protein structure. 

The β-actin protein is necessary for maintaining the shape and function of stereocilia, whereas its absence results in high-frequency hearing loss and stereocilia degeneration, roles not compensated by γ-actin.

The ACTB gene’s β-actin protein also contributes to transport along microtubules, highlighting the protein’s critical role in cellular transport mechanisms.

ACTB in Health and Disease

Baraitser-Winter Syndrome (BWS) [7.] 

The ACTB gene encodes the β-actin protein, a crucial component of the cytoskeleton involved in cell motility, structure, integrity, and intercellular signaling. 

β-actin, along with γ-actin encoded by ACTG1, is highly expressed in nonmuscle cells and plays essential roles in various cellular functions. 

These proteins exist in monomeric (G-actin) and polymeric (F-actin) forms, contributing to processes such as muscle contraction, cytokinesis, chromatin remodeling, and transcription regulation.

Mutations in ACTB can cause Baraitser-Winter Syndrome (BWS), a developmental disorder characterized by distinctive craniofacial features, intellectual disability, ocular colobomata (congenital eye defects characterized by missing pieces of tissue in structures of the eye), and neuronal migration defects. 

BWS is primarily caused by spontaneous mutations in both the ACTB and ACTG1 genes, with common mutations such as ACTB p.Arg196His and ACTG1 p.Ser155Phe being identified in affected individuals. 

These mutations lead to specific structural and functional disruptions in β-actin and γ-actin, resulting in the clinical manifestations of BWS.

Genetic studies involving affected individuals and their unaffected parents have confirmed the association of these de novo mutations with BWS. 

The mutations result in increased F-actin content and altered F-actin dynamics affecting cell morphology, motility, and other actin-related functions. 

In patients with BWS, these mutations lead to phenotypic features such as:

• Congenital ptosis: a drooping or falling of the upper eyelid that is present at birth.  It may affect one or both eyes, and it may partially or completely cover the pupil, potentially impacting vision. 

• High-arched eyebrows

• Hypertelorism: an increased distance between the inner corners of the eyes

• Pachygyria: abnormally thick convolutions (gyri) of the brain, which are more pronounced at the anterior brain.  It results in a smooth brain surface with fewer folds than normal, and is often associated with developmental delays and seizures

The impact of ACTB mutations extends beyond the cytoskeletal functions to involve developmental processes. 

The presence of recurrent mutations at specific sites like Arg196 in β-actin suggests a gain-of-function or dominant-negative effect, as these sites are critical for the protein's function. 

Consequently, BWS patients also exhibit a range of developmental abnormalities, including short stature, microcephaly, intellectual disability, hearing loss, and seizures.

Overall, the ACTB gene and its encoded β-actin protein play vital roles in maintaining cellular and developmental functions, and mutations in this gene lead to significant clinical and pathological features in Baraitser-Winter Syndrome.

Dystonia-Deafness Syndrome 1 [2., 8.] 

Dystonia-deafness syndrome 1 (DDS1) is an autosomal dominant neurological disorder characterized by sensorineural deafness in childhood, followed by progressive dystonia. 

This dystonia primarily affects the bulbar region, leading to speech difficulties (dysarthria) and swallowing problems (dysphagia). 

Some individuals also exhibit dysmorphic features (abnormal differences in body structure, typically present from birth), skeletal anomalies, and mild developmental delays with impaired intellectual development. 

DDS1 is linked to striatal abnormalities; severity varies among individuals, with cases of intractable dystonia sometimes leading to death in the second or third decades.

Juvenile-onset dystonia, a form of DDS1, involves sustained involuntary muscle contractions, abnormal postures, and sensory hearing loss, with symptoms typically emerging in late childhood or early adolescence.

Mutations in the ACTB gene, particularly the p.Arg183Trp mutation, are highly implicated in DDS1. This mutation affects the β-actin protein, essential for cell structure and function, including cell adhesion, migration, cytokinesis, and maintenance of cell polarity.

Case Study 1: A 19-Year-Old Girl [8.] 

A 19-year-old girl with the ACTB p.Arg183Trp mutation illustrates the impact of this gene on DDS1. She was born with mild facial abnormalities and severe hearing loss from infancy, along with mild cognitive and emotional disabilities. 

During adolescence, she developed severe, generalized dystonia characterized by involuntary muscle contractions and abnormal postures.

Brain imaging revealed reduced function in the striatum, a brain region involved in movement control, and lower dopamine receptor activity, indicating dopaminergic dysfunction. 

Treatment with deep brain stimulation (DBS) significantly improved her condition, reducing the severity of her dystonia and enhancing her quality of life. Whole exome sequencing confirmed the presence of the ACTB p.Arg183Trp mutation, which disrupts normal actin function essential for various cellular processes. 

Additionally, the mutation affects synaptic activity in the brain, especially during puberty when the striatum undergoes significant changes.

Case Study 2: A 52-Year-Old Brazilian Woman [3.] 

A 52-year-old Brazilian woman presented with generalized dystonia and progressive sensorineural hearing loss since early childhood. 

Born from non-related parents, she had developmental delays, poor language acquisition, and epilepsy. At age 25, she developed dystonia, beginning in her left lower limb and progressing to other body regions, eventually becoming wheelchair-bound by age 47. 

Whole-exome sequencing identified the ACTB p.Arg183Trp mutation. Despite various treatments, including levodopa, biperiden, and clonazepam, her dystonia showed minimal improvement.

Juvenile-Onset Dystonia [4.] 

Mutations in ACTB can lead to disorders such as Baraitser-Winter Syndrome 1 and Dystonia-Deafness Syndrome 1, highlighting its critical role in cellular functions and development.

In the context of juvenile-onset dystonia, the aggregation of actin and cofilin, an actin-associated protein, has been observed in identical twins with a unique progressive neurodegenerative disorder. 

These twins developed generalized dystonia, characterized by severe muscle contractions and abnormal postures, beginning at age 12. 

Neuropathological examination revealed eosinophilic rod-like and spherical cytoplasmic inclusions in the brain, predominantly composed of actin and ADF/cofilin. These inclusions were present in the neocortex, thalamus, and striatum, suggesting a novel mechanism of neurodegeneration involving actin aggregation.

Electron microscopy confirmed the presence of actin microfilaments in these inclusions, marking the first report of actin aggregation as a primary neuropathological feature in a neurodegenerative disease. 

The dysfunction in the twins appeared to extend beyond actin protein to the regulatory system governing actin filament turnover, implicating the ADF/cofilin pathway. 

These findings suggest that dysregulation of the actin cytoskeleton and its associated proteins may play a significant role in the pathology of certain neurodegenerative diseases, providing new insights into the underlying mechanisms of juvenile-onset dystonia and other related disorders.

Cancer [5.] 

New insights are surfacing regarding ACTB in cancer.  

Beta-actin (ACTB), traditionally regarded as a housekeeping gene, plays crucial roles in various cellular processes, including cell migration, division, and gene expression. 

However, recent research has shown that ACTB is closely associated with many cancers, such as liver, melanoma, renal, colorectal, gastric, pancreatic, esophageal, lung, breast, prostate, ovarian cancers, leukemia, and lymphoma. 

Generally, ACTB is up-regulated in most tumor cells and tissues. [5.] Its abnormal expression and polymerization contribute to changes in the cytoskeleton, which are linked to the invasiveness and metastasis of cancer cells. 

ACTB polymerization at the leading edge of migrating cells provides the forces needed for cell movement, aiding in cancer spread. 

Understanding ACTB's role in cancer could provide insights into new therapeutic targets and strategies for cancer treatment.

In summary, ACTB, beyond being a housekeeping gene, plays a significant role in cancer pathogenesis, particularly in promoting tumor invasiveness and metastasis, highlighting the importance of carefully considering its use as a reference gene in cancer research and exploring its potential as a therapeutic target. [5.] 

Genetic Alterations in the ACTB Gene

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

While many SNPs have been researched regarding alterations in function of the ACTB gene, these two commonly appear in literature.  

p.Arg183Trp [3., 8.] 

The mutation p.Arg183Trp in the ACTB gene refers to a specific change in the β-actin protein encoded by this gene. This change occurs in a highly conserved region of the actin protein, likely affecting its structure or function.

This mutation has been associated with Baraitser-Winter syndrome 1 (BWS) and Dystonia-Deafness Syndrome 1, rare developmental disorders.

p.Arg196His (c.587G>A) [9.] 

This mutation is one of the most common and recurrent mutations in patients with BWS. It affects a critical arginine residue, leading to significant functional changes in β-actin. 

Laboratory Testing for ACTB

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: Understanding the ACTB Gene, Protein and Genetic Test

What is ACTB?

ACTB stands for Beta-Actin, a protein that is crucial for maintaining the cell's cytoskeleton structure. It is encoded by the ACTB gene and plays a significant role in cell motility, structure, integrity, and intracellular transport.

What is the Function of ACTB?

The primary function of ACTB (Beta-Actin) is to provide structural support to cells. It forms part of the cytoskeleton, helping maintain the cell's shape and enabling movements such as migration and division. 

ACTB is also involved in various cellular processes, including signal transduction and gene expression.

What is the ACTB Gene?

The ACTB gene encodes the Beta-Actin protein. It is highly conserved across species and is located on chromosome 7 in humans. The ACTB gene is often used as a reference gene in gene expression studies due to its consistent expression across different tissues and conditions.

Why is ACTB Used as a Reference Gene in Research?

ACTB is commonly used as a reference gene in research because of its stable and ubiquitous expression in most cell types. This makes it an ideal control for normalizing data in gene expression studies, ensuring the accuracy and reliability of experimental results.

How is ACTB Measured?

ACTB is generally assessed as a genetic test to determine whether specific genetic alterations are present. 

What are the Clinical Implications of Altered ACTB Expression?

Altered ACTB expression can be indicative of various diseases and conditions, including cancer, cardiovascular diseases, and neurodegenerative disorders. Changes in ACTB levels can affect cellular functions and contribute to the pathogenesis of these diseases.

How does ACTB Relate to Cancer Research?

In cancer research, ACTB is often studied for its role in cell motility and metastasis. Overexpression or mutations in ACTB can lead to abnormal cell migration and invasion, contributing to cancer progression and metastasis. However, research is still being performed to understand the implications of ACTB in cancer pathogenesis.

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