Uncovering the genetic roots of metal metabolic disorders

Next-generation sequencing sheds light on genetic disorders associated with metals, paving the way to new therapeutic approaches.

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Molecular-level high-throughput gene sequencing could help spot specific mutations responsible for metal metabolic disorders and develop new treatments, suggest KAIMRC researchers.

Metal and metalloid nutrients play a pivotal role in many structural and functional processes in the body. Although these biological processes only require infinitesimal quantities of nutrients, any imbalance causes numerous health problems. KAIMRC’s Majid Alfadhel, one of the two authors of the study, explains that metal ions imbalances are linked to several abnormalities, including cardiovascular diseases, metabolic disorders, and neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases. 

Specifically, insufficient amounts of nutrients in the daily diet and metabolic disorders lead to deficiencies that can trigger mild to serious health issues. An excess of metal nutrients from food, or exposure to toxic metals promotes build-up in tissues and organs, especially in the brain, also results in adverse health effects and impedes normal processes.

Metabolic disorders related to metals originate from defects in the proteins and enzymes involved in nutrient metabolism and energy production. Most of these defects stem from single-gene mutations. For example, Wilson disease results from more than 700 mutations of a single gene, which hinders copper excretion and produces copper toxicity in the liver and central nervous system. However, recent next-generation sequencing studies contradict this ‘one gene–one enzyme’ concept.

Alfadhel and Muhammad Umair have surveyed the latest genetic research on various metal-related metabolic disorders. “We were able to highlight an ignored area of biomedical research, and focus on genes that may be key to develop targeted treatment,” says Alfadhel.

The researchers revealed that mutations in multiple genes may lead to the same phenotype. Specifically, different disorders associated with zinc imbalance, such as acrodermatitis enteropathica and transient neonatal zinc deficiency, involve several mutations of genes coding the same zinc transporter protein family, but show similar symptoms. Hereditary hemochromatosis, which causes severe iron accumulation in the liver and pancreas, is associated with mutations in five different genes involved in the production of hepcidin, a protein that regulates iron absorption in the intestinal track.

Individuals with hybrid phenotypes might show mutations in more than two genes that generate more than two phenotypes. This gives rise to complex genetic disorders that are difficult to diagnose and manage with a therapeutic plan. Specifically, inborn neurodegenerative disorders linked to brain iron accumulation arise from multiple genes, but only two of the identified genes control iron metabolism.  These inherited disorders also share analogous pathways with other neurodegenerative diseases, including Parkinson’s and Alzheimer’s. Similarly, selenium-related metabolic disorders are extremely complex and are associated with mutations in the genes encoding for selenoproteins, which mediate redox reactions, thyroid hormone metabolism, and iodine removal.

This insight into metal metabolism, regulation, and function could foster innovative therapeutic strategies. “Reviewing the subject as a whole will open the horizon to connect the pieces and conduct more research that may help develop treatments,” the researchers say.

References

  1. Umair, M. & Alfadhel, M. Genetic disorders associated with metal metabolism. Cells 8, 1598 (2019). | article

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