ASS1

The ASS1 gene, located on chromosome 9q34.1, encodes the enzyme argininosuccinate synthetase (ASS1), which plays a crucial role in the urea cycle and arginine biosynthesis. 

Mutations in the ASS1 gene lead to Citrullinemia Type I, an autosomal recessive disorder characterized by hyperammonemia and the accumulation of toxic substances in the blood. 

Over 137 mutations in the ASS1 gene have been identified, including 64 novel ones, with common mutations such as p.Gly390Arg, p.Arg157His, and p.Val263Met found in various populations globally. 

Clinically, Citrullinemia Type I presents in both severe neonatal forms, with symptoms like lethargy, poor feeding, and seizures, and milder adult-onset forms, characterized by headaches and ataxia. 

Diagnosis involves biochemical assays, genetic testing, and clinical evaluation, with treatments focusing on dietary protein restriction, arginine supplementation, and medications to detoxify excess nitrogen. 

Additionally, ASS1 has been identified as a target for cancer therapies involving arginine and glutamine deprivation, offering potential new avenues for treatment.

What is the ASS1 Gene and Enzyme?

The ASS1 Gene

Gene Location and Structure

The ASS1 gene is located on chromosome 9q34.1 and contains 16 exons. It produces a homotetrameric enzyme, argininosuccinate synthetase.

Mutations 

There are 87 identified mutations in the ASS1 gene, 27 of which are newly reported. [3.] Mutations are found primarily in exons 3 to 15, with notable frequency in exons 5, 12, 13, and 14. 

The G390R mutation in exon 15 is most common in classical citrullinemia cases. [3.] 

Disease Association

Mutations in the ASS1 gene cause Citrullinemia Type I, an autosomal recessive disorder. 

Clinical manifestations range from severe neonatal hyperammonemia to mild or asymptomatic cases. [3.] 

Diagnosis and Studies

Initially diagnosed through biochemical and enzymatic studies, the identification of ASS1 gene mutations now involves advanced molecular genetic methods.

The ASS1 Enzyme

Function

The ASS1 enzyme, argininosuccinate synthetase, is crucial in the urea cycle and in arginine synthesis, where it catalyzes the conversion of citrulline and aspartate to argininosuccinate. [3., 5.] 

Biochemical Characteristics

Deficiency in the ASS1 enzyme leads to Citrullinemia Type I, characterized by neonatal or intermittent hyperammonemia, low plasma arginine, elevated citrulline levels in plasma and urine, and orotic aciduria. [3.] 

Enzymatic Studies

Research on ASS1 activity has shown that certain mutations correlate with clinical severity. 

However, the enzyme activity in mild versus severe cases is not always consistent, highlighting the complexity of genotype-phenotype relationships. [3.] 

Prognosis and Research

Predicting clinical outcomes based on enzyme activity remains uncertain. Continued research aims to understand how genetic, epigenetic, and environmental factors influence the clinical course of citrullinemia. [3.] 

ASS1 in Health and Disease

Citrullinemia Type 1 [1., 2.]

Citrullinemia type 1 is a rare autosomal recessive urea cycle disorder caused by mutations in the ASS1 gene, leading to defects in the enzyme argininosuccinate synthetase (ASS). 

This condition results in hyperammonemia and the accumulation of toxic substances in the blood. 

Clinically, it manifests in two primary forms: the neonatal form and the adult-onset form. 

The neonatal form presents shortly after birth with symptoms such as lethargy, poor feeding, vomiting, seizures, and possible loss of consciousness. 

In contrast, the adult-onset form presents with variable hyperammonemia and less severe neurological symptoms like headaches, ataxia, and lethargy.

Over 137 mutations in the ASS1 gene have been identified, including 64 novel mutations. 

These mutations are found across diverse populations, including individuals from the Indian subcontinent, Turkey, Germany, and Japan. 

Citrullinemia type 1 is typically detected through newborn screening and confirmed by additional genetic and medical tests. Diagnostic strategies involve biochemical assays, genetic testing, and clinical evaluation.

Treatments for citrullinemia type 1 typically involve dietary protein restriction, supplementation of arginine, and medications to detoxify surplus nitrogen. 

This disorder affects individuals worldwide, necessitating comprehensive clinical data collection to understand its genetic and clinical spectrum fully. Ongoing research aims to better understand the genetic background and effects of mutations and to develop effective therapies for managing citrullinemia type 1.

Cancer Therapy [5.] 

The ASS1 enzyme catalyzes the conversion of citrulline and aspartate to argininosuccinate, a crucial step in the urea cycle and arginine biosynthesis.

Many tumors depend on extracellular arginine due to the silencing of ASS1, making the enzyme a target for arginine-deprivation therapies. ASS1 also acts as a sensor for glutamine deprivation.

Reduced ASS1 expression in tumors is associated with increased sensitivity to arginine and glutamine deprivation. Conversely, upregulation of ASS1 expression confers resistance to these treatments.

Research has demonstrated that the addition of permeable fumarate, which connects the tricarboxylic acid and urea cycles, downregulates ASS1 expression and increases sensitivity to arginine and glutamine deprivation. [5.] 

Targeting ASS1 expression and function provides a strategy for developing combination therapies that exploit arginine and glutamine metabolism in cancer treatment. This approach is under investigation in several clinical trials. [5.] 

Genetic Alterations in the ASS1 Gene

The gene for the ASS1 protein may contain alterations or mutations that cause increase or decrease of function of the ASS1 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 the ASS1 Gene [2.]

p.Gly390Arg [2., 3.] 

This is the most common mutation globally associated with Citrullinemia Type 1. [DIEZ>>>>>>>>>>>> It is associated with the severe, neonatal-onset form of citrullinemia, which can result in life-threatening hyperammonemia.

p.Arg157His [2.] 

Found mainly in patients from specific regions such as the Indian subcontinent and Turkey, this mutation is associated with severe forms of the disease.

p.Trp179Arg [2., 3.] 

Detected in patients with milder forms of the disease, often presenting asymptomatic or with only biochemical abnormalities.

p.Val263Met [2.] 

Common in patients from Germany and Japan, associated with severe phenotypes.

p.Arg304Trp [2.] 

Found in multiple independent families, associated with severe neonatal-onset forms.

p.Gly324Ser [2.] 

Associated with severe forms of the disease, found in various populations.

p.Gly362Val [2., 3.] 

Detected in patients with milder forms, often presenting with biochemical abnormalities without severe clinical symptoms.

p.Arg363Trp [2.] 

Found in multiple families, associated with severe neonatal-onset forms.

Laboratory Testing for ASS1

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.

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