6p24.1

6p24.1 is a gene locus on chromosome 6's short arm, housing genes critical for development, cardiovascular health, and immune function. 

Key genes within this locus include ADTRP, which regulates anticoagulant activity and influences coronary artery disease risk; EDN1, a potent vasoconstrictor involved in vascular tone and linked to cardiovascular diseases; PHACTR1, associated with endothelial dysfunction and coronary artery disease through inflammation and reduced nitric oxide production; and HIVEP1, a transcription factor affecting immune response and cellular functions. 

Variants within 6p24.1 can impact conditions ranging from myocardial infarction to developmental anomalies and endothelial health.

What is 6p24.1?

6p24.1 is a specific gene locus on the short arm of chromosome 6. The precise genetic structure of 6p24.1 includes several genes that play crucial roles in various biological processes, with primary impacts on development and cardiovascular health.  There is also some evidence of genes within the 6p24.1 locus affecting immune function. [6.] 

Genes Located within 6p24.1 and Their Functions

ADTRP [8.] 

ADTRP (Androgen-Dependent TFPI-Regulating Protein) is an androgen-inducible protein that regulates the expression and activity of Tissue Factor Pathway Inhibitor (TFPI), the key inhibitor of the Tissue Factor-dependent coagulation pathway on endothelial cells. 

Variations in the ADTRP gene are associated with coronary artery disease, myocardial infarction, and deep vein thrombosis. 

One of ADTRP's critical roles is in vascular development and vessel integrity, regulated through Wnt signaling and matrix metalloproteinase-9. 

ADTRP also hydrolyzes fatty acid esters of hydroxy-fatty acids (FAHFAs), which have anti-diabetic and anti-inflammatory effects, thus influencing metabolic disorders.

In endothelial cells, ADTRP is involved in regulating anticoagulant activity.

ADTRP’s expression is upregulated by androgens, which may contribute to its protective cardiovascular effects. 

Structurally, ADTRP contains six predicted transmembrane domains and is present in various tissues, including endothelial cells, lung, liver, kidney, and testis. Its expression pattern suggests a role in both embryonic development and adult vascular homeostasis. Additionally, ADTRP's palmitoylation sites are crucial for its membrane localization and function.

ADTRP's association with coronary artery disease is evidenced by the single nucleotide polymorphism (SNP) rs6903956, which correlates with decreased ADTRP expression and increased disease risk. [8.] 

Thus, understanding ADTRP’s functions and regulatory mechanisms could offer insights into therapeutic targets for cardiovascular and metabolic diseases.

EDN1 [5.] 

The EDN1 gene encodes Endothelin-1 (ET-1), a potent vasoconstrictor involved in various vascular functions. 

Endothelin-1 (ET-1), produced primarily by endothelial cells, plays a crucial role in vasoconstriction and the regulation of vascular tone by acting on vascular smooth muscle cells (VSMCs). 

This vasoconstrictive action promotes the development of atherosclerosis through vasomotor constriction, remodeling, and VSMC proliferation. 

Elevated expression of EDN1 is linked to an increased risk of coronary artery disease (CAD) and myocardial infarction due to its vasoconstrictive and proliferative effects on VSMCs. 

Interestingly, the same genetic variant that increases EDN1 expression is associated with a decreased risk of migraine, cervical artery dissection, fibromuscular dysplasia, and hypertension. [5.] 

EDN1 is also essential for vascular development and integrity, as it regulates endothelial cell function. Aberrant EDN1 expression can lead to various vascular anomalies, contributing to the pathology of multiple vascular diseases.

PHACTR1 [9.] 

PHACTR1 (phosphatase and actin regulator-1) has been identified as a critical risk gene for coronary artery disease (CAD) through genome-wide association studies (GWAS). 

It plays a significant role in mediating endothelial dysfunction, which is a key factor in the development of CAD. In studies of human aortic plaque tissues and ApoE-/- mice, PHACTR1 expression was notably higher in vulnerable plaques and under pro-inflammatory conditions, such as those induced by TNF-α, IL-1β, and oxidized LDL (oxLDL).

PHACTR1 overexpression has been shown to disrupt endothelial homeostasis by activating pathways associated with inflammation. It increases the expression of inflammatory markers via NF-κB activation, and it enhances monocyte adhesion to endothelial cells. [9.] 

Additionally, PHACTR1 overexpression reduces nitric oxide (NO) production, which is crucial for maintaining endothelial function and vasodilation.

Statins and other vasoprotective drugs have been found to decrease PHACTR1 expression, suggesting a potential therapeutic approach for preventing endothelial dysfunction and atherosclerosis by targeting PHACTR1.  [9.] 

In summary, PHACTR1 contributes to endothelial inflammation and reduced NO production, leading to endothelial dysfunction. 

Further studies are needed to fully understand the mechanisms by which PHACTR1 drives these processes and to explore potential therapeutic strategies targeting PHACTR1 in vascular diseases.

HIVEP1 [6.] 

The HIVEP1 gene encodes a transcription factor that belongs to the ZAS family, characterized by a ZAS domain.

HIVEP1 binds to the enhancer elements of several viral promoters, including those of HIV-1, SV40, and CMV, as well as in cellular promoters such as class I MHC, interleukin-2 receptor, and interferon-beta genes.

This binding suggests a role in the transcriptional regulation of both viral and cellular genes, potentially influencing T-cell activation and HIV-1 gene expression. 

The gene produces multiple isoforms, with isoforms 2 and 3 also binding to the promoter regions of interferon regulatory factor 1 and p53 genes, playing a role in their transcription regulation and potentially in apoptosis. 

HIVEP1 is associated with diseases such as attention deficit-hyperactivity disorder and immune deficiency disease, and it is related to its paralog, HIVEP2.

6p24.1 in Health and Disease

Normal Physiological Roles

Genes within the 6p42.1 locus have been associated with the following:

Cardiovascular Health [9.] 

This region contains the PHACTR1 gene (Phosphatase and Actin Regulator 1), which has been associated with coronary artery disease risk.

Endothelial Cell Function [7.] 

Recent studies have focused on the role of the 6p24.1 locus in endothelial cell biology, which is essential for good cardiovascular health.

Development [4.] 

Genes in this region are involved in regulating the development of various organs and systems, including the heart, skeleton, and craniofacial structures.

Coagulation [8.] 

The ADTRP gene, located near this region, has been reported to confer anti-coagulant protection in endothelial cells through regulation of tissue factor pathway inhibitor.

Vascular Tone [5.]

The EDN1 gene (Endothelin-1), located upstream of PHACTR1, is involved in regulating vascular tone and has implications for cardiovascular health.

6p24.1 Genes in Disease: Endothelial Dysfunction and Coronary Artery Disease [7.]

Genes within the 6p24.1 locus plays have been associated with endothelial function and coronary artery disease (CAD). 

A notable single nucleotide polymorphism (SNP) within this locus, rs6903956, is situated in the androgen-dependent tissue factor pathway inhibitor regulating protein (ADTRP) gene. 

This SNP's minor allele (A) has been linked to increased CAD risk and reduced ADTRP mRNA expression in leukocytes. 

Clinically, patients with the risk allele at rs6903956 exhibit higher numbers of circulating endothelial cells (CECs), indicating vascular injury. [5.]

Additionally, the rs6903956 SNP to inflammation and vascular damage in CAD. [7.] 

Genetic variants in the 6p24 region affect EDN1 expression, which plays a crucial role in regulating vascular tone. Alterations in EDN1 function are associated with coronary artery disease (CAD). [5.]

Variants in PHACTR1, particularly rs9349379, have been strongly associated with CAD risk through genome-wide association studies. These variants may influence endothelial function and vascular health through distal regulatory effects on EDN1. [9.]

Overall, the 6p24.1 locus, particularly through the genes ADTRP, HIVEP1, EDN1, and PHACTR1, influences endothelial function and contributes to the pathophysiology of CAD.

Chromosome 6p24.1 Deletion

Deletions in the 6p24.1 region are part of a broader set of deletions that contribute to a variety of neurological and developmental abnormalities, reinforcing the importance of this chromosomal segment in human development and behavior. [1.]

Patients with deletions in the 6p22.3-p24.3 region of chromosome 6 demonstrated a consistent association with developmental and speech delays, autism spectrum disorders (ASDs), and various congenital anomalies.  [1.]

The 6p24.1 deletion has specifically been linked to heart defects, skeletal anomalies, craniofacial abnormalities, and the Dandy–Walker malformation. [10.] 

The Dandy-Walker Malformation [2., 3.] 

Dandy-Walker Malformation (DWM), also known as Dandy-Walker Syndrome (DWS), is a rare congenital brain disorder that primarily affects the cerebellum.

In DWM, the cerebellar vermis is partially or completely absent, the cerebellum's hemispheres may be underdeveloped, and the fourth ventricle is enlarged, creating a fluid-filled space at the back of the brain. 

These structural abnormalities can cause motor deficits, such as delayed motor development, hypotonia, ataxia, muscle stiffness, and sometimes spastic paraplegia. 

Up to half of those affected may have intellectual disabilities, ranging from mild to severe, while others with normal intelligence might experience learning disabilities.

Most individuals with DWM exhibit symptoms at birth or within the first year of life, including hydrocephalus, which leads to increased head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes, and seizures. 

Additionally, DWM can be associated with congenital heart defects, eye abnormalities, tumors, skeletal malformations, and underdeveloped genitalia or kidneys. Other brain abnormalities such as agenesis of the corpus callosum, occipital encephalocele, or improper neuron migration may also be present.

In about 10 to 20 percent of cases, symptoms may not appear until late childhood or adulthood, presenting as headaches, an unsteady gait, facial palsy, increased muscle tone, muscle spasms, and mental and behavioral changes. Rarely, some individuals may exhibit no health problems related to the condition.

Genetic testing can be done in many ways to identify individuals with specific chromosomal or SNP abnormalities.  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.

Laboratory Testing for 6p24.1

Laboratory testing for 6p24.1 abnormalities plays a crucial role in diagnosing genetic disorders and assessing disease risk.  There are many methods used for laboratory testing of 6p24.1.

Overview of Testing Methods

Genetic testing involves various methodologies to analyze DNA and chromosomes for medical and research purposes. Here are the primary types:

Polymerase Chain Reaction (PCR): this technique amplifies small DNA samples to detect or measure specific genes or regions. It's widely used for identifying genetic variants associated with diseases.

DNA Sequencing:

Sanger Sequencing: once the standard for clinical DNA sequencing, this method involves marking DNA nucleotides with fluorescent dyes to read sequences. It's precise but limited to short DNA sections and one sample at a time.

Next-Generation Sequencing (NGS): this includes whole exome and whole genome sequencing, capable of analyzing millions of DNA fragments simultaneously. It's used for comprehensive genetic screening to identify mutations across all protein-coding regions (exome) or the entire genetic makeup (genome).

Cytogenetics:

‍Karyotyping: this traditional method examines the number and structure of chromosomes under a microscope, identifying abnormalities like extra chromosomes or translocations that can lead to diseases such as Down syndrome or chronic myelogenous leukemia.

Fluorescence In Situ Hybridization (FISH): FISH uses fluorescent probes to illuminate specific gene segments on chromosomes, useful for identifying gene amplifications or deletions.

Microarrays: this technology assesses DNA for duplications, deletions, or large identical DNA stretches using fluorescently labeled DNA samples hybridized on a chip, providing detailed chromosomal information.

Gene Expression Profiling: this test measures which genes are active in cells, using RNA from a tissue sample to determine gene activity. It's particularly used in cancer to guide treatment decisions based on the genes expressed by a tumor.

Each of these technologies plays a crucial role in diagnosing genetic disorders, guiding treatment decisions, and advancing our understanding of genetic diseases.

Sample Types

Samples typically include blood, saliva, or tissue samples containing DNA.  Sample collection can be as simple as performing a cheek swab or collecting saliva.

Interpretation of Test Results

Interpreting test results for 6p24.1 abnormalities requires expertise and an understanding of genetic principles. A positive result indicating a deletion or duplication in the 6p24.1 region may suggest an increased risk of certain genetic disorders or predisposition to specific health conditions. 

However, the clinical significance of these findings can vary depending on factors such as the size and location of the genetic alteration, as well as the presence of other genetic or environmental factors. 

Genetic counseling is often recommended to help patients and their families understand the implications of test results and make informed decisions regarding healthcare management and treatment options.

FAQ: Understanding 6p24.1

6p24.1 refers to a specific location on chromosome 6, which is of interest in genetic research and medicine. This FAQ section addresses common questions about 6p24.1, its significance, and its implications for health and disease.

What is 6p24.1?

6p24.1 is a cytogenetic location on the short arm (p) of chromosome 6 at position 24.1. This designation helps researchers and healthcare professionals identify specific regions of the chromosome that may be associated with various genetic conditions or traits.

Why is 6p24.1 Significant in Genetic Research?

The 6p24.1 region is significant because it contains genes and regulatory elements that may be linked to various health conditions and developmental processes. Understanding this region can help researchers identify genetic factors involved in diseases and develop targeted therapies.

What Genes are Located in the 6p24.1 Region?

The 6p24.1 region contains several genes that may play crucial roles in biological processes and disease mechanisms. For detailed information on specific genes within this region, researchers typically refer to genomic databases such as Ensembl or the UCSC Genome Browser.

How is 6p24.1 Studied in Genetic Research?

6p24.1 is studied using various genetic and genomic techniques, including:

• Whole genome sequencing: to identify variations within the region.

• Chromosomal microarray analysis: to detect duplications or deletions.

• Gene expression studies: to understand the function of genes within this region.

• Linkage analysis: to associate genetic markers with specific traits or diseases.

What Conditions are Associated with Abnormalities in the 6p24.1 Region?

Abnormalities in the 6p24.1 region can be associated with various genetic conditions, depending on the specific genes affected. These conditions may include developmental disorders, congenital anomalies, and cardiovascular disease.

Ongoing research aims to better understand these associations and their clinical implications.

How Can Abnormalities in the 6p24.1 Region be Detected?

Abnormalities in the 6p24.1 region can be detected using genetic testing methods such as:

• Karyotyping: To visualize chromosomal structure.

• Fluorescence in situ hybridization (FISH): To identify specific chromosomal regions.

• Next-generation sequencing (NGS): To detect genetic variations at a high resolution.

• Comparative genomic hybridization (CGH): To identify copy number variations.

What are the Potential Implications of a Genetic Finding in the 6p24.1 Region?

The implications of a genetic finding in the 6p24.1 region depend on the specific genes and variations involved. Potential implications can include:

• Disease risk: increased susceptibility to certain diseases.

• Developmental impact: influence on growth and development.

• Therapeutic targets: identification of potential targets for treatment.

• Genetic counseling: information for family planning and management of inherited conditions.

When Should I Consult a Healthcare Provider About 6p24.1?

You should consult a healthcare provider if genetic testing indicates an abnormality in the 6p24.1 region, or if there is a family history of genetic conditions linked to this region. A genetic counselor or medical geneticist can provide detailed information and guidance on the implications and management of such findings.

What Resources are Available for Further Information on 6p24.1?

Resources for further information on 6p24.1 include:

• Genomic databases: such as Ensembl, UCSC Genome Browser, and NCBI.

• Scientific journals: for the latest research articles.

• Genetic counseling services: for personalized information and support.

• Health organizations: such as the National Institutes of Health (NIH) and the Genetic and Rare Diseases Information Center (GARD).

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