Genetic mutation causes low sensitivity to pain

A UCL-led research team has identified a rare mutation that causes one family to have unusually low sensitivity to pain. They studied an Italian family, the Marsilis, which includes six people who have a distinctive pain response that has not been identified in any other people. "The members of this family can burn themselves or experience pain-free bone fractures without feeling any pain. But they have a normal intraepidermal nerve fibre density, which means their nerves are all there, they're just not working how they should be. We're working to gain a better understanding of exactly why they don't feel much pain, to see if that could help us find new pain relief treatments," said the study's lead author, Dr James Cox (UCL Wolfson Institute for Biomedical Research).

One in ten people experience moderately to severely disabling chronic pain, but treatments beyond common painkillers remain elusive. Understanding the causes of congenital analgesia, a rare inherited condition that reduces the capacity to feel physical pain, is one of the main areas of research that could lead to new pain relief therapies. Two other mutations causing congenital analgesia are being actively explored by researchers alongside pharmaceutical firms, but have yet to yield any breakthrough drugs.

The research team added to previous work with the Italian family to clarify the nature of their phenotype (the observable characteristics caused by their genetics) - named the Marsili syndrome after their surname - finding that they're hyposensitive to noxious heat, hyposensitive to capsaicin (in chilli peppers) and have experienced pain-free bone fractures. Using DNA from blood samples, the researchers conducted a whole exome sequencing - mapping out the protein-coding genes in the genome of each family member.

 They identified a novel point mutation in the ZFHX2 gene. The mutation alters a part of the gene's protein sequence that is normally consistent across species as variable as mice and frogs. The researchers then conducted two animal studies to understand how the gene affects pain sensations in mice. They initially used mice that had been bred with the ZFHX2 gene entirely absent, and found them to have altered pain thresholds. They then bred a new line of mice that had the relevant mutation, and those mice were notably insensitive to high temperatures.

Further analysis of the mice bearing the mutation clarified that the gene regulates a number of other genes that have previously-established connections to pain signalling. By identifying this mutation and clarifying that it contributes to the family's pain insensitivity, we have opened up a whole new route to drug discovery for pain relief. With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved.
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Regulating asprosin levels can control appetite and weight

Researchers have discovered a new hormone called asprosin, that regulates blood-glucose levels. New studies on the hormones showed that asprosin also acts on the brain, stimulating the hunger center in the hypothalamus to control appetite and body weight. This opens an intriguing possibility for developing treatments for overweight people. They discovered asprosin when studying individuals affected by a rare medical condition called neonatal progeroid syndrome.

Patients with neonatal progeroid syndrome have a mutation in the FBN1 gene that causes them to lack a small piece of the fibrillin-1 protein. In individuals without the FBN1mutation, this small piece, which we named asprosin, is cut and released into the circulation from the end of the protein.
One of the cardinal features that defines neonatal progeroid syndrome is extreme thinness or very low body weight. This allowed measurement of how much food they ate relative to the number of calories they burned every day.

Compared with individuals with normal weight, neonatal progeroid syndrome patients have abnormally low appetite.
To investigate how the mutation affected the patients' appetite, the researchers genetically engineered mice to carry the same genetic mutation the patients have. The result was mice that mimicked the human condition; they had low blood asprosin levels, low appetite and were very thin.

In the mouse model, researchers were able to reverse the low appetite by administering asprosin to the mice.
To understand how asprosin controls appetite. Asprosin interacts with neurons in the appetite center of the hypothalamus. There are two types of neurons involved in appetite control. One type, the AgRP neurons, stimulates appetite while the other type, POMC neurons, suppresses it.

Asprosin works on both types of neurons in an opposite manner; it activates appetite-stimulating AgRP neurons and it deactivates appetite-suppressing POMC neurons. The resulting effect of these two asprosin actions in the brain is an increase in appetite, a phenomenon that is deficient in individuals and mice with neonatal progeroid syndrome. The researchers also studied individuals with obesity and found that they had increased levels of blood asprosin.
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Genetic mutation linked to aortic dissection in the chest

Researchers at Umeå University in Sweden have discovered a genetic mutation that can cause dissection of the thoracic aorta.

The mutation leads to an impaired function of the smooth muscle cells of the aortic wall and cause an increased predisposition for aortic dissection.

 Aortic dissection is the bursting of an aortic aneurysm and can occur both within the chest abdomen.

Aortic dissection in the chest is a life-threatening condition that requires immediate care like emergency surgery.

The aorta usually dilates before a dissection, but people carrying the genetic mutation that we have discovered can have a dissection even with a mildly dilated aorta.