Posts tagged genetic diseases
Articles and news from the latest research reports.
Surprising culprit found in cell recycling defect
To remain healthy, the body’s cells must properly manage their waste recycling centers. Problems with these compartments, known as lysosomes, lead to a number of debilitating and sometimes lethal conditions.
Reporting in the Proceedings of the National Academy of Sciences (PNAS), researchers at Washington University School of Medicine in St. Louis have identified an unusual cause of the lysosomal storage disorder called mucolipidosis III, at least in a subset of patients. This rare disorder causes skeletal and heart abnormalities and can result in a shortened lifespan. But unlike most genetic diseases that involve dysfunctional or missing proteins, the culprit is a normal protein that ends up in the wrong place.
Image caption: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Credit: Eline van Meel, PhD)
“There is a lot of interest and study about how cells distribute proteins to the right parts of the cell,” said senior author Stuart A. Kornfeld, MD, PhD, the David C. and Betty Farrell Professor of Medicine. “Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just doesn’t stay in the right place.”
The right place, in this case, is the Golgi apparatus, the cell’s protein packaging center. The protein in question – phosphotransferase – normally resides in the Golgi, where its job is to attach address labels to proteins bound for the lysosome. There are 60 such lysosomal proteins, and all of them must be properly labeled if they are to end up in a lysosome, where they recycle waste.
Image caption: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Credit: Eline van Meel, PhD)
Kornfeld and his colleagues, including first author Eline van Meel, PhD, postdoctoral research associate, showed that the phosphotransferase protein responsible for adding the address label starts out in the Golgi as it should, but seems to lack the signal to keep it there.
“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it’s recaptured and sent back,” Kornfeld said. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded.”
Because phosphotransferase gradually wanders away from the Golgi, a low level of lysosomal enzymes end up being properly addressed, but at perhaps 20 percent of the normal amount.
“In many lysosomal storage disorders, such as Tay-Sachs or Gaucher’s disease, only one out of the 60 enzymes is missing from the lysosome,” Kornfeld said. “But the mislocalization of phosphotranferase causes the misdirection of all 60 lysosomal enzymes.”
While the errant phosphotransferase ends up being degraded in the lysosome, the resulting misdirected lysosomal proteins end up in the bloodstream. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal. But because some get to the lysosome at a low level, people with mucolipidosis III don’t have the most severe form of the disease.
“Type III patients live into adulthood, but they’re very impaired,” said Kornfeld. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”
Having implicated wayward phosphotransferase in this lysosomal storage disorder, Kornfeld and his colleagues are investigating what goes wrong that allows it to escape the Golgi.
“We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back,” said Kornfeld. “Now we’re trying to understand how that works.”
(Source: news.wustl.edu)
Human brain is divided on fear and panic
When doctors at the University of Iowa prepared a patient to inhale a panic-inducing dose of carbon dioxide, she was fearless. But within seconds of breathing in the mixture, she cried for help, overwhelmed by the sensation that she was suffocating.
The patient, a woman in her 40s known as SM, has an extremely rare condition called Urbach-Wiethe disease that has caused extensive damage to the amygdala, an almond-shaped area in the brain long known for its role in fear. She had not felt terror since getting the disease when she was an adolescent.
In a paper published online Feb. 3 in the journal Nature Neuroscience, the UI team provides proof that the amygdala is not the only gatekeeper of fear in the human mind. Other regions—such as the brainstem, diencephalon, or insular cortex—could sense the body’s most primal inner signals of danger when basic survival is threatened.
“This research says panic, or intense fear, is induced somewhere outside of the amygdala,” says John Wemmie, associate professor of psychiatry at the UI and senior author on the paper. “This could be a fundamental part of explaining why people have panic attacks.”
If true, the newly discovered pathways could become targets for treating panic attacks, post-traumatic stress syndrome, and other anxiety-related conditions caused by a swirl of internal emotional triggers.
“Our findings can shed light on how a normal response can lead to a disorder, and also on potential treatment mechanisms,” says Daniel Tranel, professor of neurology and psychology at the UI and a corresponding author on the paper.
Scientists Map Initial Anti-Aging Formula
A new study indicates that scientists have found a new way of delaying the aging process in mice, and they hope to replicate the finding in people.
The scientists published their findings in the journal Cell Metabolism. The research was built upon an earlier study that shed light on progeria, a rare genetic disease that prematurely ages one in four million babies.
A mutation was found in the Lamin A protein, which lines the nucleus in human cells, disrupting the repair process and accelerating aging. They also found that normal and healthy Lamin A binds to and activates the gene SIRT1, which has been long associated with longevity. If scientists can develop drugs that mimic Lamin A or increase the binding between Lamin A and SIRT1, this may lead to anti-aging drugs.
The team also examined if the binding efficiency was boosted with resveratrol, a compound found in the skin of red grapes. Mice fed with concentrated resveratrol fared significantly better than healthy mice that weren’t given it and the onset of aging was delayed and the life expectancy was extended. Mice with progeria lived 30% longer when fed with resveratrol compared with progerial mice not given the compound.
Genetic diseases diagnosed within 50 hours
The new technology screens the whole genome of the baby from a drop of their blood before homing in on abnormalities in single genes that could explain their ill health.
Genetic diseases are thought to affect up to one in a hundred children and are one of the leading causes of admission to intensive care units immediately after birth.
In about 500 of the conditions - including Krabbe disease, a nervous system disorder - early treatment can prevent the development of severe disability and life-threatening symptoms.
Most of the diseases are extremely rare and many are unfamiliar to doctors, but analysing a baby’s genes to find the cause of their condition currently takes up to six weeks.
Researchers from Children’s Mercy Hospital in Kansas City said this could be cut down to 50 hours using the new method, described in the Science Translational Medicine journal.