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Attacks of King George III's madness linked to key metabolism molecule

ited mutations that disrupt the body's manufacture of heme. A reddish pigment that contains iron, heme is a building block of the oxygen-carrying hemoglobin in red blood cells. The complex synthesis requires eight different enzymes, and when any of them is deficient because of a mutation, the process is blocked. The resulting back up of "precursor" substances is toxic, and can cause a range of symptoms, including dark colored urine, abdominal pain, nausea, vomiting, constipation, weakness in the limbs, and psychiatric symptoms such as confusion, fits and hallucinations.

Earlier this year, the British journal Lancet published a report saying that a test of strands of George III's hair contained arsenic, which can provoke porphyria attacks. The authors of that report suggested that, ironically, he may have been exposed to arsenic contamination of a substance his doctors gave him as treatment.

PGC-1 alpha is a "transcriptional coactivator" that acts as an on-off switch for a number of genes involved in manufacture of glucose in the liver and in the "heating system" of brown fat cells that help prevent damage from cold in certain animals.

With their intimate knowledge of PGC-1 alpha and its varied roles in energy metabolism, the Dana-Farber researchers wondered if it might be involved in porphyria, since PGC-1 alpha is a regulator of heme manufacture in the liver. One of its actions is controlling the activity of the ALAS-1 gene that makes a protein that's crucial to the normal manufacture of heme. A defect in this genetic signaling pathway could cause ALAS-1 to accumulate in high levels, leading to the symptoms of porphyria attacks.

"We found that PGC-1 alpha is an important factor controlling the expression of ALAS-1 in the fasted and fed liver," the authors write. "Moreover, we showed that hepatic [in the liver] PCG-1 alpha is a major determinant of the severity of acute porphyric attacks in mouse models of chemical porphyria."

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Source:Dana-Farber Cancer Institute


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