ALDH3A2

The ALDH3A2 gene encodes the enzyme fatty aldehyde dehydrogenase (FALDH), an NAD+-dependent enzyme responsible for oxidizing long-chain aldehydes into fatty acids. 

As a member of the aldehyde dehydrogenase (ALDH) family, FALDH plays a crucial role in detoxifying aldehydes produced during alcohol metabolism and lipid peroxidation. 

Additionally, FALDH is involved in the metabolism of sphingosine 1-phosphate (S1P), converting the S1P degradation product hexadecenal to hexadecenoic acid, a vital step in the S1P-to-glycerolipid metabolic pathway. This pathway is conserved across yeast and mammals, highlighting its fundamental biological importance. 

Although ALDH3A2 is present in various tissues, its highest expression is found in the liver, with lower levels in the intestine, stomach, kidney, lung, brain, and skin. 

The enzyme is vital for maintaining cellular health by preventing the accumulation of toxic aldehydes, emphasizing its significance in both normal physiology and disease states.

What is ALDH3A2? [1., 3., 5.] 

The ALDH3A2 gene encodes an enzyme known as fatty aldehyde dehydrogenase (FALDH), an NAD+-dependent enzyme that oxidizes long-chain aldehydes into fatty acids. FALDH is a member of the ALDH (alcohol dehydrogenase) family.  

Like all members of the ALDH family, FALDH is important in detoxifying aldehydes generated by alcohol metabolism and lipid peroxidation. 

FALDH is also implicated in the metabolism of sphingosine 1-phosphate (S1P). 

Specifically, it converts the S1P degradation product hexadecenal to hexadecenoic acid, a crucial step in the S1P-to-glycerolipid metabolic pathway. This pathway is conserved between yeast and mammals, indicating its fundamental biological importance.

While present in most tissues, ALDH3A2 is expressed in highest concentrations in the liver.  It is also expressed at lower levels in intestine, stomach, kidney, lung, brain, and skin compared to the liver. 

As a member of the ALDH family of enzymes, ALDH3A2 is important in maintaining cellular health and preventing the accumulation of toxic aldehydes.

ALDH3A2 In Health and Disease

Sjögren-Larsson syndrome [4., 5.] 

Sjögren-Larsson syndrome (SLS) is a genetic disorder affecting fatty alcohol metabolism due to mutations in the ALDH3A2 gene. Patients with SLS exhibit neurological and physical impairments due to fatty alcohol accumulation. 

Specific conditions associated with this neurocutaneous disorder include congenital ichthyosis (dry, scaly skin that appears soon after birth), mental retardation, and spasticity.  Retinal crystalline inclusions are pathognomonic for SLS. Brain MRI shows white matter disease, with patients typically living into adulthood. [6.] 

The pathology of SLS is thought to be due to the accumulation of fatty aldehydes.

This accumulation can cause cellular damage due to the reactivity of aldehydes with cellular components.

Gastric Carcinoma [7.] 

ALDH3A2 emerged as a novel prognostic biomarker for gastric adenocarcinoma. 

One study found that high expression of ALDH3A2 was associated with improved overall survival (OS) in gastric cancer (GC) patients. [7.] Immunohistochemical analysis of 140 human GC samples confirmed that ALDH3A2 expression was higher in low-grade tumors. 

Additionally, ALDH3A2 was negatively correlated with immune checkpoints PDCD1, PDCD1LG2, and CTLA-4, suggesting its potential in influencing immune responses and enhancing the efficacy of immunotherapy. 

Genetic Alterations in the ALDH3A2 Gene

The gene for the ALDH3A2 protein may contain alterations or mutations that cause increase or decrease of function of the ALDH3A2 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 ALDH3A2 Function [2.] 

c.943C>T (p.Pro315Ser)

This is one of the most commonly reported mutations in SLS, especially in Swedish patients.  It renders the enzyme nonfunctional, which manifests as SLS.  

c.1297_1298delGA (p. Glu433Argfs*3)

This mutation is commonly found in European patients and is also associated with a single haplotype, indicating it likely originated from recurrent mutational events.

c.798G>C (p. Lys266Asp)

This mutation causes only a mild reduction in FALDH activity. Four mutations involving nucleotides around nt 798 have been identified, resulting in disrupted normal splicing or unstable mRNA.

Laboratory Testing for ALDH3A2

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: ALDH3A2 (Aldehyde Dehydrogenase 3 Family Member A2)

What is ALDH3A2?

ALDH3A2 (Aldehyde Dehydrogenase 3 Family Member A2) is an enzyme that belongs to the aldehyde dehydrogenase family. 

It is involved in the detoxification of aldehydes, which are byproducts of alcohol metabolism and lipid peroxidation, converting them into less harmful acids.

What is the Function of ALDH3A2 in the Body?

ALDH3A2 plays a crucial role in:

• Detoxification: converting toxic aldehydes into their corresponding carboxylic acids, thus protecting cells from oxidative stress and damage.

• Metabolism: participating in the metabolism of various endogenous and exogenous substances, including drugs and environmental toxins.

What is ALDH3A2 Deficiency?

ALDH3A2 deficiency is a genetic condition caused by mutations in the ALDH3A2 gene, leading to reduced or absent enzyme activity. This deficiency can result in the accumulation of toxic aldehydes in the body, causing various health problems.

What are the Symptoms of ALDH3A2 Deficiency?

Symptoms of ALDH3A2 deficiency can include:

• Dry, scaly skin (ichthyosis)

• Neurological issues, such as developmental delays or intellectual disability

• Liver dysfunction

• Ocular problems, such as photophobia (sensitivity to light)

How is ALDH3A2 Deficiency Diagnosed?

ALDH3A2 deficiency is diagnosed through genetic testing to identify mutations in the ALDH3A2 gene. Additionally, enzyme activity assays and biochemical tests can measure the levels of aldehydes and their metabolites in the blood and tissues.

What are the Health Implications of ALDH3A2 Deficiency?

ALDH3A2 deficiency can lead to a range of health issues, including:

• Neurological disorders: developmental delays and intellectual disabilities due to the accumulation of toxic aldehydes in the brain.

• Skin disorders: conditions like ichthyosis, characterized by dry, scaly skin.

• Liver disease: liver dysfunction caused by the buildup of toxic substances.

• Eye problems: sensitivity to light and other ocular issues.

How is ALDH3A2 Deficiency Managed?

Management of ALDH3A2 deficiency involves:

• Symptom management: treating skin conditions with moisturizers and other dermatological treatments.

• Supportive care: providing therapies for developmental and neurological issues.

• Regular monitoring: regular check-ups with healthcare providers to monitor liver function and overall health.

Can Lifestyle Changes Affect ALDH3A2 Deficiency?

While lifestyle changes cannot directly affect the genetic basis of ALDH3A2 deficiency, certain measures may help improve quality of life:

• Skincare: regular use of moisturizers and avoiding harsh skin products can help manage ichthyosis.

• Healthy diet: A balanced diet that supports overall health and reduces oxidative stress.

• Avoiding alcohol and certain drugs: Minimizing exposure to substances that can produce toxic aldehydes and exacerbate symptoms.

Where Can I Find More Information About ALDH3A2 and Related Conditions?

For more information about ALDH3A2 and related conditions, consider consulting:

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

• Scientific literature: research articles and reviews on ALDH3A2 and its role in metabolism and health.

• Reputable health organizations: websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and American Society of Human Genetics (ASHG).

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