Posts tagged genetic disorders
Posts tagged genetic disorders
Scientists from the University of Sheffield have paved the way for new treatments for a common genetic disorder thanks to pioneering research on zebrafish – an animal capable of mending its own heart.
Charcot Marie Tooth disease (CMT) is the most common genetic disorder affecting the nervous system. More than 20,000 people in the UK suffer from CMT, which typically causes progressive weakness and long-term pain in the feet, leading to walking difficulties. There is currently no cure for CMT.
A research project conducted at the Sheffield Institute for Translational Neuroscience (SITraN) and the MRC Centre for Developmental and Biomedical Genetics (CDBG) by Dr Andrew Grierson and his team has revealed that zebrafish could hold the key to finding new therapeutic approaches to treat the condition.
Dr Grierson said: “We have studied zebrafish with a genetic defect that causes CMT in humans. The fish develop normally, but once they reach adulthood they start to develop difficulties swimming.
"By looking at the muscles of these fish we have discovered that the problem lies with the connections between motor neurons and muscle, which are known to be essential for walking in humans and also swimming in fish."
CMT represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1), a process which causes damage to the myelin sheaths that surround our neurons, or distal axon degeneration (CMT2) of motor and sensory neurons. The distal axon is the terminal where neurotransmitter packages within neurons are docked.
The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2), which is an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. Mitochondria are known as the cellular power plants because they generate most of the supply of adenosine triphosphate (ATP), which is used as a source of chemical energy.
Dr Grierson said: “Previous work on this disorder using mammalian models such as mice has been problematic, because the mitofusin genes are essential for embryonic development. Using zebrafish we were able to develop a model with an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2.
"Motor neurons are the largest cells in our bodies, and as such they are highly dependent on a cellular transport system to deliver molecules through the long nerve cell processes which connect the spinal cord to our muscles. We already know that defects in the cellular transport system occur early in the development of diseases such as Alzheimer’s disease, Motor Neuron Disease and spastic paraplegia. Using our zebrafish model we have found that similar defects in transport are also a key part of the disease process in CMT."
Dr Grierson and his team are now seeking funding to identify new treatments for CMT using the zebrafish model. Because of their size and unique biology, zebrafish are ideal to be used in drug screens for the identification of new therapies for untreatable human conditions.
(Image courtesy: University College London)
The human face might look very different in the future.
Artist and researcher Nickolay Lamm from U.K. discount site MyVoucherCodes.co.uk collaborated with a genomics expert to create pictures that show the evolution of the human face 20,000, 60,000, and 100,000 years from now.
In one possible future scenario, humans will have full control of human genome engineering. That is, they will be able to eliminate hereditary genetic disorders, or select desirable genetic traits like straight teeth and natural blonde hair.
Natural human evolution is still at work — the head will get bigger to make room for a larger brain — but most facial features will be molded to reflect what the majority of us perceive as attractive: big eyes, a straight nose, and facial symmetry.
From the neurons that enable thought to the keratinocytes that make toenails grow-a complex canopy of sugar molecules, commonly known as glycans, envelop every living cell in the human body.
These complex carbohydrate chains perform a host of vital functions, providing the necessary machinery for cells to communicate, replicate and survive. It stands to reason, then, that when something goes wrong with a person’s glycans, something goes wrong with them.
Now, researchers at the University of Georgia are learning how changes in normal glycan behavior are related to a rare but fatal lysosomal disease known as Niemann-Pick type C (NPC), a genetic disorder that prevents the body from metabolizing cholesterol properly. The findings were published recently in the PNAS Early Edition.
"We are learning that the problems associated with cholesterol trafficking in the cell lead to problems with glycans on the cell’s surface, and that causes a multitude of negative effects," said Geert-Jan Boons, professor of chemistry in the Franklin College of Arts and Sciences and researcher at UGA’s Complex Carbohydrate Research Center. "Now, for the first time, we can see what these problems are, which we hope will lead to a new understanding of diseases like NPC."
Because NPC patients are unable to metabolize cholesterol, the waxy substance begins to accumulate in the brain. This can lead to a host of serious problems, including neurodegeneration, which the researchers hypothesize may be caused by improper recycling of glycans on the surface of an NPC patient’s cells.
Glycans normally undergo a kind of recycling process when they enter the cell only to be returned to the surface recharged and ready to work. The researchers discovered that glycans in NPC cells do not do this.
"One of the secondary effects of NPC is the disruption of traffic pathways within the cell, and this can lead to altered recycling of glycans," said Richard Steet, associate professor of biochemistry and molecular biology and CCRC researcher. "The glycans come into the cell, but they won’t recycle back up to the cell’s surface where they must exist to function as receptors or ion channels."
"Basically, the machinery gets clogged up," Boons said.
Like downed phone lines and flooded roads in a thunderstorm, glycans get stuck inside the cell making communication and travel for these cells difficult or impossible. Without these basic abilities, the body’s motor, sensory and cognitive functions begin to suffer. This might explain why NPC patients suffer from such a wide variety of neurological and psychiatric disorders, such as uncoordinated limb movements, slurred speech, epilepsy, paralysis, psychosis, dementia and hallucinations.
The researchers made these observations in fibroblasts taken from diseased patients. These cells are most commonly found in connective tissues, and they play a vital role in wound healing. However, they hope to continue their investigation into the effects of NPC by studying glycan behavior in neural cells, which make up the human brain.
While they caution that much more work must be done, they hope that an improved understanding of the roles that glycans play in neural cells will lead to new therapeutics for NPC and other diseases like it.
"It is exciting to work on projects like these, because we believe glycobiology is the next frontier, the next level of complexity," Boons said. "The time is right for new discovery."
Giant axonal neuropathy (GAN) is a rare genetic disorder that causes central and peripheral nervous system dysfunction. GAN is known to be caused by mutations in the gigaxonin gene and is characterized by tangling and aggregation of neural projections, but the mechanistic link between the genetic mutation and the effects on neurons is unclear. In this issue of the Journal of Clinical Investigation, Robert Goldman and colleagues at Northwestern University uncover how mutations in gigaxonin contribute to neural aggregation.They demonstrated that gigaxonin regulates the degradation of neurofilament proteins, which help to guide outgrowth and morphology of neural projections. Loss of gigaxonin in either GAN patient cells or transgenic mice increased levels of neurofilament proteins, causing tangling and aggregation of neural projections. Importantly, expression of gigaxonin allowed for clearance of neurofilament proteins in neurons. These findings demonstrate that mutations in gigaxonin cause accumulation of neurofilament proteins and shed light on the molecular pathology of GAN.
Our time in the womb is one of the most vulnerable periods of our existence. Pregnant women are warned to steer clear of certain foods and alcohol, and doctors refrain from medical interventions unless absolutely necessary, to avoid the faintest risk of causing birth defects.
Yet it is this very stage that is now being considered for some of the most daring and radical medical procedures yet devised: stem cell and gene therapies. “It’s really the ultimate preventative therapy,” says Alan Flake, a surgeon at the Children’s Hospital of Philadelphia in Pennsylvania. “The idea is to avoid any manifestations of disease.”
The idea may sound alarming, but there is a clear rationale behind it. Use these therapies on an adult, and the body part that you are trying to fix is fully formed. Use them before birth, on the other hand, and you may solve the problem before it even arises. “This will set a new paradigm for treatment of many genetic disorders in future,” says Flake.
Flake has been performing surgery on unborn babies for nearly 30 years, using techniques refined on pregnant animals to ensure they met the challenges of working on tiny bodies and avoided triggering miscarriage. The first operation on a human fetus took place in 1981 to fix a blocked urethra, the tube that carries urine out of the bladder. Since then the field has grown to encompass many types of surgery, such as correction of spinal cord defects to prevent spina bifida.
While fetal surgery may now be mainstream, performing stem cell therapy or gene therapy in the womb would arguably be an order of magnitude more challenging. Yet these techniques seem to represent the future of medicine, offering the chance to vanquish otherwise incurable illnesses by re-engineering the body at the cellular level. Several groups around the world are currently testing them out on animals in the womb.
Of the two, stem cell therapy has the longer history: we have been carrying it out on adults since the 1950s, in the form of bone marrow transplants. Bone marrow contains stem cells that give rise to all the different blood cells, from those that make up the immune system to the oxygen-carrying red blood cells. Bone marrow transplants are mainly carried out to treat cancers of immune cells, such as leukaemia, or the various genetic disorders of red blood cells that give rise to anaemia.
One of Flake’s interests is sickle-cell anaemia, in which red blood cells are distorted into a sickle shape by a mutation in the gene for haemoglobin. People with the condition are usually treated with blood transfusions and drugs to ease the symptoms, but even so they may well die in their 40s or 50s. Some are offered a bone marrow transplant, although perhaps only 1 in 3 can find a donor who is a good match genetically and whose cells are thus unlikely to be rejected by their body. “The biggest issue with treating disease with stem cells is the immune system,” says Flake.
And therein lies the main reason for trying a bone marrow transplant in an unborn baby: its immune system is not fully formed. At around the fourteenth week of pregnancy, the fetus’s immune system learns not to attack its own body by killing off any immune cells that react to the fetus’s own tissues. This raises the prospect of introducing donor stem cells during this learning window and so fooling the immune system into accepting those cells. “You can develop a state of complete tolerance to the donor,” says Flake. “If it works for sickle cell, then there are at least 30 related genetic disorders that could be treated.”
These glowing shapes aren’t the ears of a rave-happy Vulcan - they’re slices from a mouse’s brain.
The slice on the right is from a mouse that lacks a gene called Arl13b - the same gene whose mutation causes Joubert syndrome in humans. This is a rare neurological condition that is linked with autism-spectrum disorders and brain structure malformations.
Without Arl13b, the nerve cells known as interneurons can’t find the right destination in the cerebral cortex during the brain’s development. Since the interneurons don’t end up in the right places, they can’t be wired up properly later on. This causes the disrupted brain development, typical of Joubert syndrome, visible in the image on the right.
The researchers hope that their findings will lead to better treatments for people who have the syndrome.
"Ultimately, if you’re going to come up with therapeutic solutions, it’s important to understand the biology of the disease," says Eva Anton of the University of North Carolina in Chapel Hill, who worked on the research, which was published in Developmental Cell last week.
The Hazards of Growing Up Painlessly
The girl who feels no pain was in the kitchen, stirring ramen noodles, when the spoon slipped from her hand and dropped into the pot of boiling water. It was a school night; the TV was on in the living room, and her mother was folding clothes on the couch. Without thinking, Ashlyn Blocker reached her right hand in to retrieve the spoon, then took her hand out of the water and stood looking at it under the oven light. She walked a few steps to the sink and ran cold water over all her faded white scars, then called to her mother, “I just put my fingers in!” Her mother, Tara Blocker, dropped the clothes and rushed to her daughter’s side. “Oh, my lord!” she said — after 13 years, that same old fear — and then she got some ice and gently pressed it against her daughter’s hand, relieved that the burn wasn’t worse.
“I showed her how to get another utensil and fish the spoon out,” Tara said with a weary laugh when she recounted the story to me two months later. “Another thing,” she said, “she’s starting to use flat irons for her hair, and those things get superhot.”
Tara was sitting on the couch in a T-shirt printed with the words “Camp Painless But Hopeful.” Ashlyn was curled on the living-room carpet crocheting a purse from one of the skeins of yarn she keeps piled in her room. Her 10-year-old sister, Tristen, was in the leather recliner, asleep on top of their father, John Blocker, who stretched out there after work and was slowly falling asleep, too. The house smelled of the homemade macaroni and cheese they were going to have for dinner. A South Georgia rainstorm drummed the gutters, and lightning illuminated the batting cage and the pool in the backyard.
Without lifting her eyes from the crochet hooks in her hands, Ashlyn spoke up to add one detail to her mother’s story. “I was just thinking, What did I just do?” she said.
Scientists have cracked a molecular code that may open the way to destroying or correcting defective gene products, such as those that cause genetic disorders in humans.
The code determines the recognition of RNA molecules by a superfamily of RNA-binding proteins called pentatricopeptide repeat (PPR) proteins.
When a gene is switched on, it is copied into RNA. This RNA is then used to make proteins that are required by the organism for all of its vital functions. If a gene is defective, its RNA copy and the proteins made from this will also be defective. This forms the basis of many terrible genetic disorders in humans.
RNA-binding PPR proteins could revolutionise the way we treat disease. Their secret is their versatility - they can find and bind a specific RNA molecule, and have the capacity to correct it if it is defective, or destroy it if it is detrimental. They can also help ramp up production of proteins required for growth and development.
The new paper in PLOS Genetics describes for the first time how PPR proteins recognise their RNA targets via an easy-to-understand code. This mechanism mimics the simplicity and predictability of the pairing between DNA strands described by Watson and Crick 60 years ago, but at a protein/RNA interface.
Children with a rare syndrome that includes a form of insulin-dependent diabetes have brain abnormalities that appear to set the stage for cognitive problems later in life, according to new research at Washington University School of Medicine in St. Louis.
The scientists studied children with Wolfram syndrome, which causes insulin-dependent diabetes in childhood. The disorder also causes hearing and vision loss and kidney problems. As patients get older, they can develop cognitive difficulties and dementia, and more than half die before their 30th birthday.
ScienceDaily (July 5, 2012) — A gene whose mutation results in malformed faces and skulls as well as mental retardation has been found by scientists.
They looked at patients with Potocki-Shaffer syndrome, a rare disorder that can result in significant abnormalities such as a small head and chin and intellectual disability, and found the gene PHF21A was mutated, said Dr. Hyung-Goo Kim, molecular geneticist at the Medical College of Georgia at Georgia Health Sciences University.
The scientists confirmed PHF21A’s role by suppressing it in zebrafish, which developed head and brain abnormalities similar to those in patients. “With less PHF21A, brain cells died, so this gene must play a big role in neuron survival,” said Kim, lead and corresponding author of the study published in The American Journal of Human Genetics. They reconfirmed the role by giving the gene back to the malformed fish — studied for their adeptness at regeneration — which then became essentially normal. They also documented the gene’s presence in the craniofacial area of normal mice.
While giving the normal gene unfortunately can’t cure patients as it does zebrafish, the scientists believe the finding will eventually enable genetic screening and possibly early intervention during fetal development, including therapy to increase PHF21A levels, Kim said. It also provides a compass for learning more about face, skull and brain formation.
The scientists zeroed in on the gene by using a distinctive chromosomal break found in patients with Potocki-Shaffer syndrome as a starting point. Chromosomes — packages of DNA and protein — aren’t supposed to break, and when they do, it can damage genes in the vicinity.
"We call this breakpoint mapping and the breakpoint is where the trouble is," said Dr. Lawrence C. Layman, study co-author and Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. Damaged genes may no longer function optimally; in PHF21A’s case it’s about half the norm.
"When you see the chromosome translocation, you don’t know which gene is disrupted," Layman said. "You use the break as a focus then use a bunch of molecular techniques to zoom in on the gene." Causes of chromosomal breaks are essentially unknown but likely are environmental and/or genetic, Kim said.
Little was known about PHF21A other than its role in determining how tightly DNA is wound in a package with proteins called histones. How tightly DNA is wound determines whether proteins called transcription factors have the access needed to regulate gene expression, which is important, for example, when a gene needs to be expressed only at a specific time or tissue. PHF21A is believed to primarily work by suppressing other genes, for example, ensuring that genes that should be expressed only in brain cells don’t show up in other cell types, Kim said.
Next steps include using PHF21A as a sort of geographic positioning system to identify other “depressor” genes it regulates then screening patients to look for mutations in those genes as well. “We want to find other people with different genes causing the same problem,” Layman said, and they suspect the genes PHF21A interacts with or regulates are the most likely suspects. It’s too early to know what percentage of Potocki-Shaffer syndrome patients have the PHF21A mutation, Kim noted. “Now that we know the causative gene, we can sequence the gene in more patients and see if they have a mutation,” Layman said.
They also want to look at less-severe forms of mental deficiency, including autism, for potentially milder mutations of PHF21A. More than a dozen of the 25,000 human genes are known to cause craniofacial defects and mental retardation, which often occur together, Kim said.
Source: Science Daily