Thyroid Hormone Transporters — Functions and Clinical Implications

Thyroid Hormone Transporters

Thyroid hormones regulate many metabolic and developmental processes, including key having functions in the brain, and mutations in a transporter specific for thyroid hormone leads to severe neurological impairment. This review article attempts to discuss the physiological importance and clinical implications of thyroid hormone transport, with a particular focus on brain development.

The thyroid hormones, T4 (3,5,3′,5′tetraiodo-L-thyronine) and T3 (3,5,3′tri-iodo-L-thyronine; also known as tri-iodothyronine) are iodinated amino acids produced and secreted by the thyroid gland. These hormones regulate many developmental and metabolic processes. The nuclear T3 receptors are ligand-modulated transcription factors encoded by two genes, THRA and THRB. These genes encode several receptor proteins, of which three (thyroid hormone receptor α1, thyroid hormone receptor β1 and thyroid hormone receptor β2) interact with T3, which results in tissue-specific and developmentally-dependent transcriptomic changes. In the developing cerebral cortex, 500–1,000 genes are directly or indirectly affected by thyroid hormones. In addition, both T4 and T3 perform nongenomic, extranuclear actions. For example, T3 might interact with a plasma-membrane-associated thyroid hormone receptor α variant, and with cytoplasmic thyroid hormone receptor β, while T4 interacts with integrin αvβ3 and activates diverse signalling pathways such as the phosphoinositide 3-kinase pathway and mitogen-activated protein kinase pathways.

Metabolism of thyroid hormones includes the processes of deiodination, deamination, decarboxylation, sulphation and glucuronidation, which have been extensively reviewed elsewhere. The most relevant pathway for the discussion in this Review is deiodination, a process that activates or inactivates thyroid hormones. Deiodinases are selenoproteins that catalyze the removal of specific iodine atoms from the phenolic or tyrosyl rings of the iodothyronine molecule. Type 1 iodothyronine deiodinase and type 2 iodothyronine deiodinase (DIO1 and DIO2, encoded by the DIO1 and DIO2 genes, respectively) have phenolic, or 'outer' ring, activity and convert T4 to T3. In extrathyroidal tissues, this pathway generates ∼80% of the total body pool of T3. Type 3 iodothyronine deiodinase (DIO3, encoded by the DIO3 gene) and DIO1 have tyrosyl, or 'inner' ring, activity and convert T4 and T3 to the inactive metabolites 3,3′5′-triiodo-L-thyronine (rT3) and 3,3′-diiodo-L-thyronine (T2), respectively; rT3 is then further metabolized by DIO1 to T2.

• Many proteins can mediate thyroid hormone transport, but only mutations in genes encoding MCT8, MCT10 and OATP1C1 have pathophysiological effects attributed to this process

• MCT8 mutations lead to Allan–Herndon–Dudley syndrome, which is characterized by truncal hypotonia and results in spastic quadriplegia, lack of speech, severe intellectual deficit and altered thyroid hormone concentrations

• MCT8 deficiency impairs the transfer of thyroid hormones across the blood–brain barrier

• Mct8-deficient mice lack neurological impairment possibly due to the presence of Oatp1c1, a T4 transporter, but levels of OATP1C1 in the primate blood–brain barrier are very low

• Histopathological studies of patients with mutations in MCT8 support the concept that defective thyroid hormone action in the brain during development leads to the neurological syndrome

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Melanoma May Be Stoppable With Drug That Halts Cancer Cell Proliferation

A drug already being tested in people as a treatment for cancer appears to show great promise in halting melanoma skin cancer. The drug - called pevonedistat - works in a way differently than intended and could also be effective against other cancers.

So says a new study from the University of Virginia School of Medicine in Charlottesville that was published in the journal EBioMedicine.

Lead researcher Tarek Abbas, assistant professor of radiation oncology, says:

"In fact, the drug is very effective on all melanomas, including those for which an effective therapeutic is lacking."

Melanoma is an aggressive skin cancer that develops when melanocytes - the cells that give skin its color - mutate and become cancerous.

Read more: Melanoma May Be Stoppable With Drug That Halts Cancer Cell Proliferation

Melanoma is an aggressive skin cancer that develops when cells that give skin its color mutate and
become cancerous. The researchers say they have found a drug that may stop the cancer progressing.

Source: MedicalNewsToday

Crohn's disease: Potential treatment to prevent fibrosis uncovered

Scientists from the University of British Columbia in Canada have found a mutation that switches off a hormone receptor, which prevents mice from developing fibrosis. This discovery could lead to potential treatments to prevent fibrosis in people with Crohn's disease.

Inflammatory bowel disease (IBD) - which includes Crohn's disease and ulcerative colitis - affects around 1.6 million people in the United States. Most people are diagnosed with Crohn's disease before age 35, and while these life-long conditions can be treated, there is currently no cure.

Crohn's disease is a long-term condition that causes inflammation to the lining of the digestive system. While the disease can affect any part of the gastrointestinal tract, the most commonly affected areas are the end of the small intestine (the ileum) or the large intestine (colon).

Read more: Crohn's disease: Potential treatment to prevent fibrosis uncovered

Scientists can potentially block complications of fibrosis in Crohn's disease by dampening particular
inflammatory cell types.

Source: medicalnewstoday

Watch: Discovery offers hope for Crohn's disease sufferers

Vitamin D and Autism: The Missing Link

Causes, Prevention, and Treatment

I first became interested in vitamin D when I learned that it is not a vitamin. Instead, it is the only known substrate of a seco-steroid neuro-hormone that functions, like all steroids, by turning genes on and off.

That means it has as many different mechanisms of action as the genes it regulates. Moreover, vitamin D directly regulates hundreds, if not thousands, of the 21,000 coding genes of the human genome. Genes are responsible for making the proteins and enzymes the human body relies on for normal development and function.

Evidence that vitamin D is involved in the autism epidemic is mounting.

Read more: Vitamin D and Autism: The Missing Link

Source: naturalsolutionsmag

How Seizures Affect the Body

Having a seizure can be an alarming experience, and whether yours have been mild or severe, you probably have many questions. Understanding what’s happening to your brain and how it’s affecting your body can be helpful and comforting for you and your loved ones as you learn more about managing your condition.

Epilepsy Symptoms

Epilepsy is a neurological disorder, which affects some or all functions of your brain. It can be caused by mutated genes, brain injury or disease. Since your brain controls everything from movement and balance to memory and emotions, an epileptic episode can disrupt this activity, resulting in a seizure or other unusual behaviors or sensations.

Read more: How Seizures Affect the Body

Source: healthguides

Watch: Myths About Epilepsy

Breast Cancer: Existing Drug Shows Promise for Prevention in High-Risk Women

Researchers have identified an existing drug that they say has the potential to prevent or delay breast cancer for women at high risk of developing the disease.

In a study published the journal Nature Medicine, researchers reveal how the drug denosumab halted the growth of pre-cancerous cells in breast tissue of women with a faulty BRCA1 gene.

Women with a BRCA1 gene mutation are at significantly greater risk for breast and ovarian cancers; around 55-65 percent of women with such a mutation will develop the disease by the age of 70, according to the National Cancer Institute, compared with 12 percent of those in the general population.

Read more:  Breast Cancer: Existing Drug Shows Promise for Prevention in High-Risk Women

Researchers found the drug denosumab stopped the growth of cells that are a precursor to breast cancer
in women with a BRCA1 gene mutation.

Source: medicalnewstoday

New gene testing method can identify mutations, prioritize variants in breast and ovarian cancer genes

A research team led by an award-winning genomicist at Western University has developed a new method for identifying mutations and prioritizing variants in breast and ovarian cancer genes, which will not only reduce the number of possible variants for doctors to investigate, but also increase the number of patients that are properly diagnosed.

These potentially game-changing technologies, developed by Peter Rogan, PhD, students and his collaborators from Western's Schulich School of Medicine & Dentistry, reveal gene variants that were missed by conventional genetic testing.

Their method, described in BMC Medical Genomics, was first applied to 102 individuals at risk or with a diagnosis of inherited breast cancer. The team also studied 287 women with no known mutations for an article published in Human Mutation.

Rogan, Canada Research Chair in Genome Bioinformatics, says that 16 to 20 per cent of women in southwestern Ontario, who have their BRCA genes tested for breast and/or ovarian cancer risk, carry disease-causing gene variants that are well-understood by clinicians and genetic counselors. If a patient tests positive for an abnormal BRCA1 or BRCA2 gene and have never had breast cancer, there is a much higher-than-average risk of developing the deadly disease.

Read more: New gene testing method can identify mutations, prioritize variants in breast and ovarian cancer genes

Source: azonano