ACER3

The ACER3 gene, located on chromosome 11, encodes the enzyme alkaline ceramidase 3 (ACER3), which is vital for ceramide metabolism.  Ceramides are essential lipid molecules involved in cell proliferation, myelination, and immune response regulation. 

Mutations in the ACER3 gene can lead to a deficiency in enzyme activity, causing the accumulation of ceramides and contributing to various pathological conditions including ACER3-related leukoencephalopathy, Parkinson's disease (PD), and cancer.

Specific single nucleotide polymorphisms (SNPs) such as p.Glu33Gly (E33G) and c.53T>C (p.Leu18Pro) are associated with the loss of ACER3 activity and result in severe neurological conditions.  

Understanding the ACER3 gene and enzyme is crucial for diagnosing and managing disorders related to its dysfunction, with advances in genetic testing providing valuable insights for targeted therapies and improved patient outcomes.

The ACER3 Gene and Protein

The ACER3 gene, located on chromosome 11 in humans, codes for the ACER3 (alkaline ceramidase 3) enzyme, which is involved in the metabolism of ceramides.  Ceramides are important lipid molecules involved in various cellular processes. 

Biological Functions of the ACER3 Gene and Enzyme  [1., 4., 6.]

ACER3 (Alkaline Ceramidase 3) is a protein-coding gene involved in myelination, cell proliferation, and sphingolipid metabolism.  ACER3 plays a role in neuron survival and immune response modulation by controlling ceramide and sphingosine-1-phosphate levels. 

The ACER3 enzyme is an alkaline ceramidase that catalyzes the hydrolysis of unsaturated long-chain ceramides such as C18:1 and C20:1 into free fatty acids and sphingosine.  It is one of the three alkaline ceramidase enzymes found in humans, along with ACER1 and ACER2.

Mutations in the ACER3 gene can lead to a deficiency in ACER3 enzyme activity, resulting in the accumulation of unsaturated long-chain ceramides.  This accumulation has been associated with various pathological conditions, including neurological disorders and metabolic diseases. 

Alterations in ACER3 function are linked to hepatocellular carcinoma and non-alcoholic steatohepatitis, as well as progressive leukodystrophy and neurogenic bladder.  [7.]

Diseases Associated with ACER3

ACER3-Related Leukoencephalopathy  [2.]

ACER3-related leukoencephalopathy is a progressive neurological disorder characterized by white matter abnormalities in the brain, leading to various neurological symptoms.  It is caused by homozygous mutations in the ACER3 gene, resulting in the accumulation of unsaturated long-chain ceramides and alterations in myelination.

Symptoms may include developmental delay, intellectual disability, spasticity, ataxia, seizures, and progressive neurological deterioration

ACER3 and Parkinson’s Disease  [6.]

Alterations in ACER3 function can significantly impact ceramide metabolism, contributing to the pathogenesis of Parkinson's disease (PD). 

Ceramides, bioactive lipids involved in cell signaling and membrane stability, are metabolized by enzymes like ACER3.  Inherited deficiencies in ACER3 disrupt ceramide metabolism, leading to the accumulation of various sphingolipids.

Parkinson's disease is characterized by the aggregation of misfolded α-synuclein proteins, often linked to lysosomal dysfunction.  

ACER3 deficiencies result in elevated levels of ceramides and complex sphingolipids, which are implicated in α-synuclein aggregation. This aggregation is a hallmark of PD and contributes to the neurodegeneration seen in the disease.

Studies have highlighted that mutations in ceramide-metabolizing genes, including ACER3, are associated with an increased risk of PD.  The accumulation of sphingolipids due to ACER3 deficiency leads to lysosomal dysfunction, promoting the aggregation of α-synuclein and ultimately contributing to neuronal cell death.

ACER3 and Cancer  [5.]

Alterations in ACER3 function have significant implications for cancer cell regulation due to its role in sphingolipid metabolism.  

ACER3 hydrolyzes ceramides into sphingosine.  This process is crucial for maintaining a balance between ceramide and sphingosine-1-phosphate (S1P), two bioactive lipids with opposing roles in cell fate: ceramide promotes cell death, while S1P supports cell survival.

Deficiency or dysfunction of ACER3 leads to an accumulation of its ceramide substrates, which can disrupt normal cellular processes.

Elevated ceramide levels resulting from ACER3 deficiency can enhance apoptosis and inhibit cell proliferation, providing a potential mechanism for cancer suppression and enhanced effectiveness of chemotherapy and radiotherapy. 

For instance, ceramide generation is essential for the apoptotic response to chemotherapeutic agents like daunorubicin and radiation.  Elevated serum levels of ceramide have been associated with improved responses to combination therapies in clinical trials. 

Furthermore, the ceramide accumulation due to ACER3 dysfunction can interfere with S1P-mediated signaling pathways which are critical for cancer cell survival, proliferation, and metastasis.

Genetic Alterations in the ACER3 Gene

The gene for the ACER3 protein may contain alterations or mutations that cause increase or decrease of function of the ACER3 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 Altered Function of ACER3

p.Glu33Gly (E33G)  [3.]

Homozygous mutations of p.Glu33Gly (E33G) in the ACER3 gene have been reported to inactivate the catalytic function of the ACER3 enzyme.  This mutation abolishes the enzyme's activity, causing an accumulation of ceramides and other sphingolipids in the patients' blood.

Deficiencies in the ACER3 gene can lead to a novel form of childhood leukodystrophy characterized by developmental regression, leukodystrophy, and peripheral neuropathy. 

This condition was identified in Ashkenazi-Jewish patients who exhibited symptoms between 6-13 months of age. 

The patients showed increased levels of ceramides and sphingolipids, lipid accumulations that are linked to neurological impairments including hypotonia, spasticity, dystonia, optic disc pallor, peripheral neuropathy, and neurogenic bladder.  MRI scans showed progressive white matter changes consistent with leukodystrophy.

c.53T>C (p.Leu18Pro) and c.292T>C (p.Tyr98His)

Both of these SNPs in ACER3 are associated with loss of enzymatic activity, disrupted protein structure/function, and clinical phenotypes like progressive leukodystrophy.   [2.]

Laboratory Testing for ACER3

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. 

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.

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