ABCC6

ABCC6, also known as ATP-binding cassette sub-family C member 6, plays a crucial role in cellular transport processes and has garnered attention for its significance in various diseases.

The importance of ABCC6 genetic testing lies in its involvement in drug transport and disease pathology. 

By understanding ABCC6 expression levels and activity, clinicians can gain insights into disease mechanisms, predict treatment responses, and optimize therapeutic strategies.

What is ABCC6?  [3.] 

ABCC6, also referred to as ATP-binding cassette sub-family C member 6, is a membrane-bound transporter protein encoded by the ABCC6 gene.  Belonging to the MRP subfamily of the ATP-binding cassette (ABC) transporter superfamily, ABCC6 plays a pivotal role in cellular transport processes, particularly the efflux of molecules across cell membranes.

ABCC6 is an efflux pump primarily expressed in the liver and kidneys. Structurally, it features two transmembrane domains and two cytoplasmic nucleotide-binding domains typical of ABC transporters.  

Studies have revealed its capability to transport substrates like the glutathione conjugate N-ethylmaleimide and leukotriene C4, albeit with lower affinity compared to other transporters. 

Otherwise, the exact endogenous substrates of ABCC6 remain elusive, complicating our understanding of its role in diseases. However, it is now recognized as a member of calcification regulators.  

ABCC6 deficiency is considered the leading factor driving ectopic mineralization (calcium deposition in the skin and soft tissues) observed in diseases like pseudoxanthoma elasticum (PXE).  [3.] 

It may also be associated with β-thalassemia and generalized arterial calcification of infancy (GACI) in humans.  [3.]  Mutations have also been implicated in multidrug resistance.   [1.] 

Mutations in ABCC6 can lead to defective protein localization and function, contributing to the pathogenesis of PXE and related conditions. Despite efforts to identify its substrates, uncertainties persist, warranting further investigation into ABCC6's physiological role and potential therapeutic targets.

The gene for the ABCC6 protein may contain alterations or mutations that cause loss of function of the enzymes and can confer increased risk of disease in affected humans.  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.

Functions of ABCC6

Understanding of the function of ABCC6 in health and disease is expanding as it is increasingly targeted in research.  

ABCC6 and Pseudoxanthoma Elasticum (PXE)  [4.]

Pseudoxanthoma elasticum (PXE) is characterized by skin, ocular, and cardiovascular manifestations. 

Cutaneous lesions, including small yellowish papules and leathery plaques, are observed primarily on the neck and flexural areas. Histological examination reveals calcium deposition in affected tissues. 

Ocular manifestations involve mottling of the retina, angioid streaks, and progressive central vision loss. 

Cardiovascular symptoms include arterial calcification and increased risk of cardiovascular disease. 

Diagnosis typically involves histological examination and genetic testing. Despite various therapeutic approaches, there is no systemic therapy to slow PXE progression. 

The role of ABCC6 in PXE is multifaceted, with hypotheses suggesting its involvement in metabolic dysfunction, altered biosynthesis, and extracellular ATP release. Common mutations in ABCC6 associated with PXE include R1141X, exon 23-29 deletion, R1164X, and Q378X, with some mutations leading to impaired function critical for preventing tissue mineralization.

ABCC6 and Multidrug Resistance  [2.]

Alterations in ABCC6 have been implicated in multidrug resistance, particularly in cancer therapy. While ABC transporters play crucial roles in maintaining cellular physiology by facilitating substrate transport, they are also involved in drug resistance mechanisms. 

ABCC6 has been shown to mediate the efflux of glutathione conjugates and confer resistance to natural anti-cancer drugs like doxorubicin and etoposide. Additionally, ABCC6 has been identified as a potential contributor to resistance to tyrosine kinase inhibitors such as nilotinib and dasatinib in Chronic Myeloid Leukaemia (CML). 

Epigenetic regulation of ABCC6 and ABCB1 expression has been observed, suggesting their involvement in drug resistance mechanisms. In glioma stem cells, increased expression of ABCC6 and ABCC3 contributes to chemotherapy resistance. 

Efforts to mitigate drug resistance have led to the identification of molecules like 2C, which reduce the efflux of doxorubicin and inhibit nucleophilic substitution reactions, highlighting potential therapeutic strategies targeting ABCC6 to overcome multidrug resistance in cancer therapy. 

These findings underscore the dual role of ABCC6 in both the genetic disease pseudoxanthoma elasticum (PXE) and resistance to anticancer agents.

Lab Testing for ABCC6

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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