ACTG1

ACTG1 encodes actin gamma 1, a crucial cytoplasmic protein essential for cell motility, structure, and signaling. 

Highly conserved across species, ACTG1 plays a fundamental role in maintaining the cytoskeleton and facilitating internal cell movement, particularly in non-muscle cells such as intestinal and inner ear hair cells. 

Mutations in ACTG1 are linked to various disorders, notably DFNA20/26, a form of autosomal dominant, progressive hearing loss, and Baraitser-Winter syndrome 2, which includes intellectual disability and distinctive facial features. 

The c.1109T>C mutation, resulting in the p.V370A amino acid substitution, significantly impairs γ-actin function, affecting cellular processes like actin polymerization and stability. 

This mutation highlights the importance of γ-actin in hearing and underscores the need for genetic screening and targeted therapies for associated conditions.

What is ACTG1? [1., 4., 11.] 

ACTG1 encodes actin gamma 1, a highly conserved cytoplasmic actin protein essential for cell motility, structure, and signaling. 

In the context of ACTG1, "highly conserved" means that the protein's structure and function have remained relatively unchanged throughout evolution. This implies that actin gamma 1 is critical for essential cellular processes, and any significant changes to its structure could be detrimental to the organism's survival and function. 

The high conservation indicates its importance across different species, reflecting its fundamental role in cell motility, structure, and integrity.

The gamma-actin protein, along with beta-actin (encoded by ACTB), is ubiquitously expressed in non-muscle cells, playing key roles in maintaining the cytoskeleton and facilitating internal cell movement. 

Actin proteins form a network of fibers known as the actin cytoskeleton, providing structural support within cells. Of the six types of actin, four are specific to muscle cells, aiding in muscle contraction. 

The remaining two, γ-actin and beta (β)-actin (encoded by the ACTB gene), are present in cells throughout the body, where they help maintain cell shape and facilitate cell movement (motility). [6.] 

γ-actin is especially abundant in certain intestinal cells and inner ear hair cells, which are crucial for normal hearing. [6.] 

Mutations in ACTG1 are linked to several disorders including DFNA20/26, or Deafness, Autosomal Dominant 20, an autosomal dominant form of non-syndromic sensorineural progressive hearing loss. 

Baraitser-Winter syndrome2, which is characterized by intellectual disability, distinctive facial features, and neuronal migration defects, is also associated with mutations in ACTG1. 

Both β-actin and γ-actin exist in monomeric (G-actin) and polymeric (F-actin) forms, crucial for cellular processes like muscle contraction, cytokinesis, and gene transcription. Understanding ACTG1's function and its related mutations provides significant insights into its role in health and disease.

ACTG1 in Health and Disease

Baraitser-Winter Syndrome 2 [10., 14.] 

Baraitser-Winter Syndrome 2 (BRWS2) is a rare developmental disorder characterized by:

• Facial dysmorphism: Distinctive features include hypertelorism (widely spaced eyes), ptosis (droopy eyelids), high-arched eyebrows, broad nose with bulbous tip, and coarsening of facial features over time.

• Ocular abnormalities: Iris and/or retinal coloboma may be present.

• Brain malformations: Pachygyria (abnormally thick cerebral cortex with fewer folds) and/or band heterotopias, often with an anteroposterior gradient.

• Intellectual disability: Ranging from mild to severe.

• Epilepsy: Often severe and potentially drug-resistant.

• Progressive joint stiffness: Particularly affecting large joints like knees, shoulders, and elbows.

• Short stature: Growth is typically mildly delayed.

BRWS2 is specifically caused by heterozygous mutations in the ACTG1 gene, which encodes gamma (γ)-actin. 

This protein is part of the actin cytoskeleton, crucial for cell structure and function. The condition is typically sporadic, resulting from de novo mutations, though autosomal dominant inheritance is theoretically possible.

Autosomal Dominant Non-Syndromic Sensorineural Progressive HearingLloss (DFNA20/26) [5.] 

ACTG1 mutations are linked to this type of hearing loss. It is characterized by high-frequency hearing loss, and patients with these mutations may be good candidates for electric acoustic stimulation.

Several genes may be responsible for autosomal dominant non-syndromic hearing loss (DFNA) including ACTG1, which is associated with DFNA20/26. 

The ACTG1 gene encodes gamma actin, a crucial protein for the cytoskeleton of auditory hair cells, essential for maintaining stereocilia. 

Mutations in ACTG1 lead to progressive high-frequency hearing loss, often starting in childhood or adolescence and potentially becoming profound by the sixth decade of life.

This type of hearing loss, characterized by a sloping audiometric configuration, underscores the importance of early genetic screening and continuous audiological follow-up to ensure timely intervention and management.

Coloboma [7., 8., 15.] 

ACTG1 mutations have been associated with coloboma, a condition affecting the eyes. Coloboma is a congenital eye condition where normal tissue is missing in one or more structures of the eye at birth. 

Coloboma can affect various parts of the eye, including the iris, retina, choroid, optic disc, lens, and eyelids. The most common and visible type is iris coloboma, which gives the pupil a keyhole or cat-eye appearance.

It can occur in one eye (unilateral) or both eyes (bilateral).

The impact on vision varies depending on the location and extent of the missing tissue, ranging from no vision problems to severe visual impairment.

Coloboma is relatively rare, affecting less than 1 in 10,000 births.

There is no cure for coloboma, but treatments are available to manage symptoms and associated vision problems

Cancer [3., 10., 12.] 

In cancer, overexpression of ACTG1 is often observed in tumor cells, where it supports increased cellular motility and invasiveness, facilitating metastasis. 

Actin proteins, including γ-actin, are involved in cell motility, division, and maintaining cell shape. 

In cancer, abnormal expression of γ-actin is associated with increased cell proliferation and metastasis, making it a potential biomarker and therapeutic target for various cancers, including skin cancer. 

For example, recent studies using machine learning and experimental validation have highlighted ACTG1's significant upregulation in skin cancer tissues, indicating its role in promoting cancer cell movement and growth through the ROCK signaling pathway. [3.] 

In addition to skin cancer, altered ACTG1 function and levels have been noted in many other cancers, including hepatocellular carcinoma, colorectal cancer, lung cancer, breast cancer, prostate cancer, and many others. [2.] 

Genetic Alterations in the ACTG1 Gene

The gene for the ACTG1 protein may contain alterations or mutations that cause increase or decrease of function of the ACTG1 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 ACTG1 Function

c.1109T>C [9., 13.] 

One study reports the novel missense mutation c.1109T>C, which results in the amino acid substitution p.V370A. [9.]  

This mutation segregates with the hearing loss in a large Norwegian family, suggesting its significant role in the development of autosomal dominant, progressive, sensorineural hearing impairment linked to the DFNA20/26 locus on chromosome 17q25.3. 

This mutation significantly affects the function of γ-actin, a major cytoskeletal protein in inner ear hair cells, through molecular modeling and yeast growth assays. 

The mutation disrupts cell growth under stress conditions and is predicted to impair actin polymerization by altering the protein's structure, particularly affecting its C-terminal tail stability. [13.] 

However, the study also highlights that ACTG1 mutations are not common in other Norwegian and Danish families with hereditary hearing impairment, suggesting that such mutations are relatively rare.

Laboratory Testing for ACTG1

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 ACTG1 Gene, Protein and Genetic Test

What is ACTG1?

ACTG1 stands for Gamma-Actin, a protein that plays a crucial role in maintaining the structure and function of the cytoskeleton in cells. 

It is encoded by the ACTG1 gene, a highly encoded gene involved in numerous cellular processes, including cell motility and integrity.

What is the Function of ACTG1?

The primary function of ACTG1 (Gamma-Actin) is to maintain the cytoskeleton's integrity, which is essential for cell shape, movement, and mechanical stability. ACTG1 is particularly important in the hair cells of the inner ear, and in some intestinal cells.

What is the ACTG1 Gene?

The ACTG1 gene provides the instructions for producing Gamma-Actin.

 Located on chromosome 17 in humans, this gene is part of the actin gene family, which is critical for various cellular functions. 

Mutations in the ACTG1 gene can lead to several disorders, particularly those affecting hearing, brain and muscle function.

Why is ACTG1 Significant in Medical Research?

ACTG1 is significant in medical research due to its fundamental role in cell structure and function. 

Understanding ACTG1's role can provide insights into various diseases, especially those related to brain and auditory functions, such as certain types of hearing loss and genetic conditions that affect brain and muscle function.

How is ACTG1 Measured?

ACTG1 is typically assessed through genetic testing to assess for the presence of certain genetic mutations.

What are the Clinical Implications of Altered ACTG1 Function?

Altered ACTG1 function can manifest as various conditions including hearing loss, brain and muscle disorders, and some cancers. Changes in ACTG1 levels can disrupt cellular functions and contribute to the pathogenesis of these diseases.

How Does ACTG1 Relate to Hearing Loss?

Mutations in the ACTG1 gene have been associated with autosomal dominant nonsyndromic hearing loss, a condition where hearing loss occurs without other associated symptoms. 

The protein's role in maintaining the structure of hair cells in the inner ear is crucial for proper auditory function.

When Should I Consult a Healthcare Provider About ACTG1-Related Concerns?

If you have symptoms or a family history of conditions related to abnormal cell structure or function, such as hearing loss or muscle disorders, consult a healthcare provider. 

They can evaluate your condition, including potential ACTG1 involvement, and recommend appropriate tests and treatments.

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