Showing posts with label AS articles. Show all posts
Showing posts with label AS articles. Show all posts
Friday, November 4, 2011
FAST Newsletter, November 2011
The latest edition of the FAST Newsletter has arrived!
November 2011, FAST Newsletter
Click the above link to read the following articles:
You had me at hello
by Debbie Guagliardo
Approaching clinical trials… “What a long, strange trip it’s been”
by Edwin J. Weeber, Ph.D.
Questions regarding the potential clinical trial
by Rebecca D. Burdine, Ph.D
Opinion piece— clinically important
by Rebecca D. Burdine, Ph.D
Meet our new postdoctoral fellows
Thoughts on the word “cure”
by Rebecca D. Burdine, Ph.D
Jamie Berkley Memorial Tournament
The turning point
by Paula M. Evans
What I did this summer
by Tina Thompson
Ready for my close-up… in the Ville
by Sharon Weil-Chalker M.D
Events and fundraisers
Monday, September 26, 2011
Angelman Syndrome Jumps from 1:15,000 Births to 1:1,500 for Babies Born Using IVF
In-vitro fertilization linked to rare genetic disorders
REUTERS / Kacper Pempel
A doctor injects sperm directly into an egg during an in-vitro fertilization (IVF) procedure in Warsaw.
Sep 25, 2011 – 9:41 PM ET
A University of Toronto geneticist is calling for more study of a link between fertility treatment and certain rare genetic disorders, noting that babies born after treatment are up to 10 times more likely to suffer from the conditions — one of which causes serious mental disability.
And that is likely just the tip of the iceberg, Dr. Rosanna Weksberg said after addressing Canada’s fertility-medicine community recently.
Dr. Weksberg said she supports in-vitro fertilization and other reproductive-technology procedures, with the “wonderful” benefits they usually bring families, but noted that she is already seeing many fertility-treatment offspring with one of the conditions show up in her genetics clinic.
Dr. Weksberg said she supports in-vitro fertilization and other reproductive-technology procedures, with the “wonderful” benefits they usually bring families, but noted that she is already seeing many fertility-treatment offspring with one of the conditions show up in her genetics clinic.
Called Beckwith-Wiedemann syndrome, causing symptoms such as unevenly sized limbs, an enlarged tongue and a high risk of kidney tumours, it occurs in one of every 1,300 such children, compared to one in 13,000 in the general population.
Further research is required, said the physician at Toronto’s Hospital for Sick Children, to deduce why the treatments sometimes trigger genetic abnormalities — though still in a relatively small number of cases — and devise ways to make the treatments safer.
“We are seeing a significant increase in risk,” she said after her presentation to the Canadian Fertility and Andrology Society conference. “The most important message is … we need follow-up study.”
As she finished her talk, the fertility doctors and scientists politely applauded, filed out to their morning break and asked no questions, a contrast to previous speakers. The apparent lack of interest was “very telling,” Dr. Weksberg admitted with a smile later.
She said she would like to partner with one or more fertility clinics to study larger populations of children born with the help of reproductive technology, though so far has no takers.
She also said one of her “biggest disappointments” was that a Supreme Court of Canada ruling late last year had ruled unconstitutional most of the federal Assisted-human Reproduction Act, since the agency set up by the law could have played a key role in spearheading such research.
A spokesman for the fertility society said the industry is, in fact, keen to get to the bottom of genetic disorders connected to its work, but no clinic could afford to fund research on its own.
“It’s a very real source of concern,” said Dr. Roger Pierson, a University of Saskatchewan fertility scientist. “We’re still in the first two generations of people born with assisted-reproduction technology … and there is lots we don’t know about them.”
The genetic conditions detailed by Dr. Weksberg include not just Beckwith-Wiedemann, but also Angelman syndrome, which can cause serious mental retardation and speech impairment, and jumps from one in 15,000 births to one in 1,500 among fertility-treatment kids, she said.
There is also evidence of an increase in the likelihood of a baby being born at a low weight, and conflicting research suggesting an increased risk of autism, she said. Other findings may well come. “It’s the tip of the iceberg,” said Dr. Weksberg.
The exact cause of the genetic problems is unknown, but is likely a combination of the biological parents’ infertility problems and genetics, and the treatments themselves, said Dr. Weksberg.
Earlier, the conference heard from a U.S. scientist who told of new innovations in diagnosing genetic problems before in-vitro fertilization is performed, and in fetuses during pregnancy.
Dr. Matthew Rabinowitz, CEO of the company Gene Security Network and originally trained in physics and engineering, entered the field only a few years ago after witnessing a relative’s traumatic experience with a baby who was born with a genetic disorder and eventually died.
He said his analysis of the genetics of embryos, using results of the human-genome project, provide a more accurate prediction of problems like Down’s syndrome than conventional testing. Similar, non-invasive genetic testing is now also possible of fetuses during pregnancy by looking for fetal DNA in the mother’s blood, he said.
“This is something we really hope will change the practice of pregnancy management around the world,” said Dr. Rabinowitz, also a professor at Stanford University.
In fact, the work is of such innovation it could one day lead to a Nobel prize, predicted Dr. Pierson, calling it “brilliance beyond the norm.”
The research also raises moral and philosophical questions, though, since the testing potentially leads to the rejection of embryos for IVF or termination of pregnancies when genetic problems like Down’s are detected, he noted.
National Post
tblackwell@nationalpost.com
tblackwell@nationalpost.com
Entire article taken from the National Post.
Thursday, August 25, 2011
Genetic Engineering Cures Mice of Brain Disorder
Genetic engineering cures mice of brain disorder
Taken from original source: VANDERBILT UNIVERSITY MEDICAL CENTER'S WEEKLY NEWSPAPER
2/09/2007 - Edwin Weeber, Ph.D., is studying Angelman syndrome. (photo by Susan Urmy)
New research in mice, however, suggests that many of these deficits could be alleviated.
Edwin Weeber, Ph.D., and colleagues reversed the neurological deficits in a mouse model of Angelman syndrome by preventing the inhibition of CaMKII, an enzyme highly expressed in brain regions affected by Angelman syndrome.
The results, which appear in the March issue of Nature Neuroscience (currently available online), reveal an important part of the mechanism underlying the condition and point to potential therapeutic targets for treating these symptoms.
Angelman syndrome, which affects approximately one in 15,000 children, is a debilitating neurological disorder characterized by mental retardation, severely limited speech, and movement and balance problems.
In 1997, researchers determined that Angelman syndrome was caused by a mutation in a single gene, called UBE3A.
They subsequently developed a mouse model of Angelman syndrome by mutating this gene.
But the finding was baffling, said Weeber, because UBE3A is a “housekeeping” gene, meaning that it broadly regulates cellular processes not particularly specific for any of the neurological deficits seen in these children. Specifically, the protein encoded by UBE3A “tags” other proteins for degradation by the cellular “garbage disposal,” the proteasome.
“The most difficult thing to rationalize was that this housekeeping gene — which nobody thought did anything — caused severe mental retardation,” said Weeber, an assistant professor of Molecular Physiology and Biophysics and Pharmacology and senior author on the study.
“So we started trying to identify some of the protein's molecular targets.”
In the process, Weeber and colleagues identified an abnormality in the Angelman syndrome mouse model — changes in an enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII), which is important in the cellular processes that underlie learning and memory.
They found that, in Angelman syndrome, CaMKII activity was reduced due to an inhibitory chemical modification (phosphorylation). Because of CaMKII's prominent role in neuronal function, Weeber suspected that this might account for many of the neurological deficits seen in Angelman syndrome children.
Fortuitously, one of Weeber's colleagues — Ype Elgersma, Ph.D., at Erasmus Medical Center in Rotterdam, Netherlands — had created a mouse with a mutation that prevented this inhibition of CaMKII.
The researchers decided to breed the Angelman mice with the CaMKII mutant mice to see if counteracting the CaMKII inhibition would alleviate the neurological problems.
The researchers then ran the resulting “double mutants” through a battery of neurological and cognitive tests.
Angelman mice performed poorly on learning and memory tasks and displayed impaired motor coordination.
The double mutants, however, showed normal learning and memory and motor coordination. And while the Angelman mice were also prone to seizures, the double mutants showed very low seizure susceptibility.
Weeber was surprised by the robust results. “We thought we might rescue some of the deficits that we saw in the mouse model,” he said. “We had no idea that we were going to rescue basically everything.”
Although impossible to apply the genetic engineering used in the current study to correct these deficits in mice to humans, Weeber thinks that the findings may point to new therapeutic targets for the disorder.
“It's very conceivable that if we can figure out what lies between UBE3A and CaMKII — and if it's a specific path — then that could be a therapeutic target.”
But the results may apply more broadly, Weeber said, to other types of mental retardation syndromes that remained unexplained and untreatable.
“There are a lot of mental retardation syndromes that we still don't understand. Maybe the changes in CaMKII associated with Angelman syndrome could be implicated in other mental retardation syndromes as well.”
Weeber is also an investigator in the Vanderbilt Kennedy Center for Research on Human Development.
Taken from original source: VANDERBILT UNIVERSITY MEDICAL CENTER'S WEEKLY NEWSPAPER
Wednesday, August 24, 2011
What my friend Bronwen and Actor Colin Farrell have in common...
Article taken from origninal source: Chester County Moms Blog
Wednesday, August 24, 2011
What my friend Bronwen and Actor Colin Farrell have in common...
This post is written by one of my oldest and dearest friends Bronwen Ward. Bron is the mother of two beautiful girls Hannah and Lily. Today is Lily's Birthday and in honor of her Birthday I wanted to share her story and help draw awareness to a cause that my friend Bron has been campaigning for the past few months.
Lily has a smile that is infectious. It’s big and bright and totally pure. Her laugh is amazing. She makes the people around her smile and laugh with her. Lily has red hair, big blue eyes, and skin so pale she is practically translucent. She looks like an angel, and she is. Lily hasAngelman Syndrome.
Angelman Syndrome (or AS) is a neurodevelopmental disorder affecting approximately 1 in 15,000 births. Although the cause of AS is known, there are currently no treatments available for this disorder
Lily was diagnosed with Angelman Syndrome at ten months old. She was diagnosed through genetic testing, after visiting multiple doctors because of reflux; physical therapists because of unmet milestones; and a general feeling of “something just isn’t right”.
When your pregnant with your second child, of course everything will be perfect. Just like the first time. Plans are made. Everyone is excited. Big sister, Hannah, has such plans for the new baby. Hannah has decided that they will be best friends, become veterinarians together, and raise their families together. Pregnancy, labor and delivery are all fine. It’s the after that’s not.
When you have a baby, there is no ceiling. The sky is the limit. Everything and anything is a possibility. After a diagnosis like Angelman Syndrome, you have to rethink your lifestyle, your life plans, your everything. I went through a mourning period. I mourned for the fact Lily would never get married, never have babies. I mourned for the fact that life would be harder for her. She would have to struggle to do the simplest tasks. I was so sad for Hannah, that her dreams for her sister would not come true. Amazingly, she told me, at the age of six, that it was alright if Lily couldn’t become a vet. Lily would live with her, and she, Hannah, would take care of Lily. I’ve discovered over time, that, you have these dreams and hopes, but they are flexible. They are ever changing. I was sad and heartbroken, but Lily was happy and loved. She helped fix me.
Lily will be six in August, and we are at the five year anniversary of our diagnosis. I say “our” because we are a unit. My husband, Adrian, my eleven year old, Hannah, myself and Lily. Having a marriage is hard already. Throw in a child with a disability, the fact that I had to quit my job so we are down to one income and the craziness of everyday life; it’s sometimes hard to keep our “unit” in working order. A sense of humor is a must. If you’re not laughing you’re crying. Sometimes we do both at the same time.
Lily has yet to walk unassisted, but is “cruising” around holding onto furniture. She was late to roll (18 months), to sit unassisted (2 ½ years), and to pull to stand (5 years). Because she is so mobile now we have to blockade her into a “lily proof zone” in the living room. She has been involved in PT and OT since she was six months old and we have seen some incredible progress. Whether it’s struggling to pick up a toy, to step sideways along the couch, or to get a cheerio into her mouth, she does not give up. Lily perseveres, and that shows her character. It may take her longer to get there, to learn the skill, but that makes the feeling all the sweeter when she does. You never take anything for granted as the parent of an Angel. Every milestone is a reason to celebrate.
Lily had her first seizure at the age of one. We were told to expect them but we didn’t know what kind she would have. Lily gets “drop” seizures, or atonic seizures. She would be happily playing one minute, and the next go limp, and crumple to the floor. It was heartbreaking to see and very upsetting and scary for her sister. We have her seizures under control with multiple medications, which we give to Lily like clockwork. When she has a break through seizure we take precautions to keep her safe until they are under control again. I consider us lucky. The Angelman community has lost Angels because of uncontrollable seizures, and that is heart breaking.
My Angel has never spoken a word, but she talks all the time. I describe it to people as chirping, squealing, and squawking. She has no problem interrupting your conversation and sometimes we just can’t get her to zip it. I sometimes have dreams where she talks to me and her voice is tiny and sweet.
Lily is tiny, only thirty pounds. It’s hard for her to gain weight because she does not eat much solid food. She is fed mostly by bottle with the occasional pick-up of cereal or diced fruit thrown in. Her GI system is in chaos. It has always been this way. She has a hard time holding down her bottles, and the tiny amounts of solids are worse. It’s reflux, the doctors say. She will out grow it. Uhh….when? They said that at a year, at three. Now they admit they have no idea why her body reacts this way. Nothing abnormal in all of the studies. This is just the way she is. So, we manage. We do a lot of laundry, and I keep meaning to steam clean the carpet more often. Frustrating, yes. But hopefully, someday, she will be able to eat what she wants, whenever she wants it.
Lily rarely sleeps. I’m not sure how much she actually gets, but somewhere between 3to 5 hours a night. She sleeps in an amazing bed that is totally safe, big and comfy. It’s high on all sides so she can’t climb out. Angels are amazing climbers. She spends the night thumping and banging around in her bed, very content with her nightlights, and African lullaby music.
Lily loves music. Heavy metal, reggae, and classic rock. She loves to “feel” it. She enjoys a good cuddle, and is the only six year old I know that will watch two hours of HGTV with me and not complain. She is always on the go and must be watched at all times. I’ve turned my back for a second and she’s chewing on my shoes by the front door, or splashing around in the toilet. Nothing is sacred in our house. If it can’t get thrown in the washer, we don’t get it. If it can’t be wiped down with a Clorox wipe, it does not enter.
I live in a world where there is no such thing as a good night sleep, where there are sleepers that zip up the back and duct tape on diapers. Where there are bite marks on all my furniture and I have a real live sock monster (yes, Lily eats socks). In my world, we don’t save for Lily’s college fund; we save for her trust fund. We don’t have play dates, we have PT. I live in a world where my eleven year old knows the names and dosages of all her sisters’ medications. It’s a crazy world; hectic, loud and sometimes smelly. I love it here. Yes, sometimes it would be great if things were a tad easier but it’s nice here.
I have a husband who loves/puts up with me. I have two beautiful daughters. Hannah, who has learned early that things don’t always turn out as planned, that you make the most of what you’ve got and that everyone is a person and deserves respect. These are things I didn’t learn until I was older, they are hard and sometimes difficult lessons to learn but she has done amazingly well. She is Lily’s protector, her cheerleader and the only one who can get Lily to eat when she is sick. Sometimes Lily will do something to annoy Hannah and I will hear the, “Mom! Lily just drooled on my ipod! Get her away me!” and I will smile because it’s a wonderful thing.
Lily is an Angel. She is a sticky, smiling, energetic, loud, and sometimes annoying Angel. She does not listen. She kicks you hard to say hello. She may nibble on you if she likes you. She gives love unconditionally and you cannot help but love her back. She is perfect just the way she is and she has made us who we are.
Bron is sharing Lily's story in hopes that you will join her in supporting Foundation for Angelman Syndrome Therapeutics (FAST) and VOTE for FAST to win a much needed grant from Vivint Gives Back Project. Winning this grant would kick-start a clinical study in humans for an FDA approved therapy that has already reversed Angelman Syndrome in a mouse.
The Foundation for Angelman Syndrome Therapeutics (FAST) is an all volunteer organization dedicated to finding a cure for Angelman Syndrome.
A few weeks ago, Golden Globe winning actor Colin Farrell discussed Angelman Syndrome and his support of FAST on Late Show with David Letterman. The actor revealed that one of his sons has been diagnosed with Angelman Syndrome.
He asked viewers to support FAST and talked about the opportunity to secure research funding money through the Vivent Gives Back Project.
Click here or on the banner above to vote for FAST. Vote today and everyday until August 27th. For help or questions on voting, click here.
Lily has a smile that is infectious. It’s big and bright and totally pure. Her laugh is amazing. She makes the people around her smile and laugh with her. Lily has red hair, big blue eyes, and skin so pale she is practically translucent. She looks like an angel, and she is. Lily hasAngelman Syndrome.Angelman Syndrome (or AS) is a neurodevelopmental disorder affecting approximately 1 in 15,000 births. Although the cause of AS is known, there are currently no treatments available for this disorder
Lily was diagnosed with Angelman Syndrome at ten months old. She was diagnosed through genetic testing, after visiting multiple doctors because of reflux; physical therapists because of unmet milestones; and a general feeling of “something just isn’t right”.
When your pregnant with your second child, of course everything will be perfect. Just like the first time. Plans are made. Everyone is excited. Big sister, Hannah, has such plans for the new baby. Hannah has decided that they will be best friends, become veterinarians together, and raise their families together. Pregnancy, labor and delivery are all fine. It’s the after that’s not.
When you have a baby, there is no ceiling. The sky is the limit. Everything and anything is a possibility. After a diagnosis like Angelman Syndrome, you have to rethink your lifestyle, your life plans, your everything. I went through a mourning period. I mourned for the fact Lily would never get married, never have babies. I mourned for the fact that life would be harder for her. She would have to struggle to do the simplest tasks. I was so sad for Hannah, that her dreams for her sister would not come true. Amazingly, she told me, at the age of six, that it was alright if Lily couldn’t become a vet. Lily would live with her, and she, Hannah, would take care of Lily. I’ve discovered over time, that, you have these dreams and hopes, but they are flexible. They are ever changing. I was sad and heartbroken, but Lily was happy and loved. She helped fix me.
Lily will be six in August, and we are at the five year anniversary of our diagnosis. I say “our” because we are a unit. My husband, Adrian, my eleven year old, Hannah, myself and Lily. Having a marriage is hard already. Throw in a child with a disability, the fact that I had to quit my job so we are down to one income and the craziness of everyday life; it’s sometimes hard to keep our “unit” in working order. A sense of humor is a must. If you’re not laughing you’re crying. Sometimes we do both at the same time.
Lily has yet to walk unassisted, but is “cruising” around holding onto furniture. She was late to roll (18 months), to sit unassisted (2 ½ years), and to pull to stand (5 years). Because she is so mobile now we have to blockade her into a “lily proof zone” in the living room. She has been involved in PT and OT since she was six months old and we have seen some incredible progress. Whether it’s struggling to pick up a toy, to step sideways along the couch, or to get a cheerio into her mouth, she does not give up. Lily perseveres, and that shows her character. It may take her longer to get there, to learn the skill, but that makes the feeling all the sweeter when she does. You never take anything for granted as the parent of an Angel. Every milestone is a reason to celebrate.
Lily had her first seizure at the age of one. We were told to expect them but we didn’t know what kind she would have. Lily gets “drop” seizures, or atonic seizures. She would be happily playing one minute, and the next go limp, and crumple to the floor. It was heartbreaking to see and very upsetting and scary for her sister. We have her seizures under control with multiple medications, which we give to Lily like clockwork. When she has a break through seizure we take precautions to keep her safe until they are under control again. I consider us lucky. The Angelman community has lost Angels because of uncontrollable seizures, and that is heart breaking.
My Angel has never spoken a word, but she talks all the time. I describe it to people as chirping, squealing, and squawking. She has no problem interrupting your conversation and sometimes we just can’t get her to zip it. I sometimes have dreams where she talks to me and her voice is tiny and sweet.
Lily is tiny, only thirty pounds. It’s hard for her to gain weight because she does not eat much solid food. She is fed mostly by bottle with the occasional pick-up of cereal or diced fruit thrown in. Her GI system is in chaos. It has always been this way. She has a hard time holding down her bottles, and the tiny amounts of solids are worse. It’s reflux, the doctors say. She will out grow it. Uhh….when? They said that at a year, at three. Now they admit they have no idea why her body reacts this way. Nothing abnormal in all of the studies. This is just the way she is. So, we manage. We do a lot of laundry, and I keep meaning to steam clean the carpet more often. Frustrating, yes. But hopefully, someday, she will be able to eat what she wants, whenever she wants it.
Lily rarely sleeps. I’m not sure how much she actually gets, but somewhere between 3to 5 hours a night. She sleeps in an amazing bed that is totally safe, big and comfy. It’s high on all sides so she can’t climb out. Angels are amazing climbers. She spends the night thumping and banging around in her bed, very content with her nightlights, and African lullaby music.
Lily loves music. Heavy metal, reggae, and classic rock. She loves to “feel” it. She enjoys a good cuddle, and is the only six year old I know that will watch two hours of HGTV with me and not complain. She is always on the go and must be watched at all times. I’ve turned my back for a second and she’s chewing on my shoes by the front door, or splashing around in the toilet. Nothing is sacred in our house. If it can’t get thrown in the washer, we don’t get it. If it can’t be wiped down with a Clorox wipe, it does not enter.
I live in a world where there is no such thing as a good night sleep, where there are sleepers that zip up the back and duct tape on diapers. Where there are bite marks on all my furniture and I have a real live sock monster (yes, Lily eats socks). In my world, we don’t save for Lily’s college fund; we save for her trust fund. We don’t have play dates, we have PT. I live in a world where my eleven year old knows the names and dosages of all her sisters’ medications. It’s a crazy world; hectic, loud and sometimes smelly. I love it here. Yes, sometimes it would be great if things were a tad easier but it’s nice here.
I have a husband who loves/puts up with me. I have two beautiful daughters. Hannah, who has learned early that things don’t always turn out as planned, that you make the most of what you’ve got and that everyone is a person and deserves respect. These are things I didn’t learn until I was older, they are hard and sometimes difficult lessons to learn but she has done amazingly well. She is Lily’s protector, her cheerleader and the only one who can get Lily to eat when she is sick. Sometimes Lily will do something to annoy Hannah and I will hear the, “Mom! Lily just drooled on my ipod! Get her away me!” and I will smile because it’s a wonderful thing.
Lily is an Angel. She is a sticky, smiling, energetic, loud, and sometimes annoying Angel. She does not listen. She kicks you hard to say hello. She may nibble on you if she likes you. She gives love unconditionally and you cannot help but love her back. She is perfect just the way she is and she has made us who we are.
Bron is sharing Lily's story in hopes that you will join her in supporting Foundation for Angelman Syndrome Therapeutics (FAST) and VOTE for FAST to win a much needed grant from Vivint Gives Back Project. Winning this grant would kick-start a clinical study in humans for an FDA approved therapy that has already reversed Angelman Syndrome in a mouse.
The Foundation for Angelman Syndrome Therapeutics (FAST) is an all volunteer organization dedicated to finding a cure for Angelman Syndrome.A few weeks ago, Golden Globe winning actor Colin Farrell discussed Angelman Syndrome and his support of FAST on Late Show with David Letterman. The actor revealed that one of his sons has been diagnosed with Angelman Syndrome.
He asked viewers to support FAST and talked about the opportunity to secure research funding money through the Vivent Gives Back Project.
Monday, August 1, 2011
Insights for autism from Angelman syndrome
Insights for autism from Angelman syndrome
Benjamin Philpot Angela Mabb Matthew Judson
19 July 2011
9:28 AM ET
Similar symptoms: Angelman syndrome is caused by a deletion in the same genomic region that is affected in some cases of autism.
The word 'autism' has unfortunately entered our common lexicon, but few people have heard of Angelman syndrome, a closely linked disorder that is also accompanied by deficits in cognition and language. Autism is frequently diagnosed in individuals with Angelman syndrome1,2.
Angelman syndrome also shares a common genetic basis with some forms of autism: disruption in the number of copies of the UBE3A gene. Studying the effects of altered UBE3A gene dosage is likely to provide insight into brain defects associated with Angelman syndrome and autism, and to suggest targets for therapies.
With the exception of sex chromosome-linked genes, one copy of every gene in the body is inherited from each of an individual's parents. People usually have both maternally- and paternally-inherited copies of these alleles, but there are some genes — termed imprinted genes — for which only one copy is functional.
UBE3A is one example of an imprinted gene. Only the allele inherited from the mother is functional in neurons, whereas the paternal allele is silenced. This silencing is mediated by epigenetics — a process in which chemical modifications to DNA alter gene expression without changing the primary sequence. Thus, expression of UBE3A in neurons is entirely dependent upon expression from the maternally-inherited allele. The most common cause of Angelman syndrome is a deletion of the maternal chromosomal region 15q11-q13, which includes the UBE3A gene. Mutations in the maternal UBE3A gene alone are sufficient to cause Angelman syndrome.
Molecular intersection:
Although multiple genes are likely to contribute to most cases of autism, one of the most genetically identifiable forms of autism is a maternal duplication of the same 15q11-q13 region3,4,5. The fact that maternal, but not paternal, duplications of this region are associated with autism implicates the UBE3A gene, because UBE3A is the only paternally imprinted gene in this region.
Although speculative and in need of rigorous testing, these observations suggest that multiple copies of the UBE3A gene can lead to 15q-linked autism. A lack of a functional UBE3A gene copy in neurons, of course, results in Angelman syndrome.
Considering the potential importance of UBE3A gene dosage in both Angelman syndrome and 15q-linked autism, there is increased interest in studying the role of UBE3A in neural functions. Surprisingly little is known about UBE3A, but this is beginning to change.
We know that UBE3A is a ubiquitin E3 ligase that is involved in the degradation of proteins via the ubiquitin-proteasome pathway. Because point mutations that eliminate UBE3A ubiquitin ligase activity are sufficient to cause Angelman syndrome, the most likely explanation for Angelman syndrome — and for 15q-linked autism — is accumulation or enhanced degradation of UBE3A targets.
There are potentially many UBE3A targets and these may be relevant to multiple signaling pathways across different brain regions and periods of brain development. In this way, inappropriate levels of UBE3A may account for the multiple hits that are believed to underlie most cases of autism. Accordingly, a clear research goal is to identify UBE3A substrates in the brain that contribute to neural dysfunction, and the resulting cognitive and behavioral deficits.
Researchers are beginning to identify these brain-specific UBE3A targets6. Last year, Michael Greenberg's laboratory at Harvard Medical School identified two protein targets of UBE3A, called ARC and EPHEXIN-5, that affect synaptic receptors — proteins involved in neurotransmission7,8.
Combined with the subtle changes in brain morphology seen in people with Angelman syndrome and autism, these observations support the idea that both are largely disorders of the synapse, the junction between neurons9.
Postmortem studies of Angelman syndrome have revealed brain region-specific reductions in the density of dendritic spines — the sites of connections between neurons. Changes in synapse density and morphology may also be common features of autism spectrum disorders10.
Common circuits:
By identifying brain regions with impaired synapses caused by inappropriate UBE3A levels, we aim to understand how disrupted circuits contribute to both Angelman syndrome and autism spectrum disorders.
Research published in the past few years indicates that lack of the UBE3A protein prevents brain circuits from strengthening in response to experiences in the mouse sensory neocortex, a brain region involved in regulating sensory perceptions11,12. For example, in mice, UBE3A is required for ocular dominance plasticity — a well-defined model in which brain circuits are refined in response to experience during a critical period of brain development.
Changes in the ability to modify brain circuits in response to experience could underlie the sensory processing and cognitive deficits associated with Angelman syndrome. Whether excessive UBE3A, as seen in 15q-linked autism, also results in altered circuit plasticity remains to be tested. We suggest that the circuits affected in Angelman syndrome are similar to those disrupted in 15q-linked autism and perhaps other autism spectrum disorders as well.
Because Angelman syndrome and 15q-linked autism result from a clear genetic cause, these disorders are comparatively more tractable for therapeutic intervention than are other forms of autism. By studying the mechanisms of UBE3A gene imprinting and the role of UBE3A in circuit development, our goal is to help pave the way for novel therapies for both disorders.
Behavioral interventions can partially restore synapse and circuit plasticity in Angelman syndrome mice12. This suggests that the mechanisms underlying synaptic plasticity remain intact in the absence of UBE3A. If the same applies to autism, then behavioral or pharmacological therapies have the potential to restore function.
The identification of pathways relevant to synapse dysfunction in Angelman syndrome and 15q-linked autism will largely be based on the identification of brain-specific UBE3A targets. It is likely that UBE3A substrates accumulate to inappropriately high levels in Angelman syndrome but are degraded to inappropriately low levels in 15q-linked autism. Pharmacological approaches could regulate key UBE3A substrates and the pathways through which they signal.
Because UBE3A targets may be too numerous to address individually, manipulating UBE3A expression levels directly is potentially a more promising therapeutic strategy. Indeed, our laboratory, together with our collaborators Mark Zylka and Bryan Roth, has been awarded a grant from the Simons Foundation, SFARI.org's parent organization, to identify ways to manipulate UBE3A levels as a treatment for autism spectrum disorders.
Benjamin Philpot is associate professor of cell and molecular physiology at the University of North Carolina School of Medicine. Angela Mabb and Matthew Judson are postdoctoral fellows in his lab.
Original source of article: Insights for autism from Angelman syndrome
Benjamin Philpot Angela Mabb Matthew Judson
19 July 2011
9:28 AM ET
Similar symptoms: Angelman syndrome is caused by a deletion in the same genomic region that is affected in some cases of autism.
The word 'autism' has unfortunately entered our common lexicon, but few people have heard of Angelman syndrome, a closely linked disorder that is also accompanied by deficits in cognition and language. Autism is frequently diagnosed in individuals with Angelman syndrome1,2.
Angelman syndrome also shares a common genetic basis with some forms of autism: disruption in the number of copies of the UBE3A gene. Studying the effects of altered UBE3A gene dosage is likely to provide insight into brain defects associated with Angelman syndrome and autism, and to suggest targets for therapies.
With the exception of sex chromosome-linked genes, one copy of every gene in the body is inherited from each of an individual's parents. People usually have both maternally- and paternally-inherited copies of these alleles, but there are some genes — termed imprinted genes — for which only one copy is functional.
UBE3A is one example of an imprinted gene. Only the allele inherited from the mother is functional in neurons, whereas the paternal allele is silenced. This silencing is mediated by epigenetics — a process in which chemical modifications to DNA alter gene expression without changing the primary sequence. Thus, expression of UBE3A in neurons is entirely dependent upon expression from the maternally-inherited allele. The most common cause of Angelman syndrome is a deletion of the maternal chromosomal region 15q11-q13, which includes the UBE3A gene. Mutations in the maternal UBE3A gene alone are sufficient to cause Angelman syndrome.
Molecular intersection:
Although multiple genes are likely to contribute to most cases of autism, one of the most genetically identifiable forms of autism is a maternal duplication of the same 15q11-q13 region3,4,5. The fact that maternal, but not paternal, duplications of this region are associated with autism implicates the UBE3A gene, because UBE3A is the only paternally imprinted gene in this region.
Although speculative and in need of rigorous testing, these observations suggest that multiple copies of the UBE3A gene can lead to 15q-linked autism. A lack of a functional UBE3A gene copy in neurons, of course, results in Angelman syndrome.
Considering the potential importance of UBE3A gene dosage in both Angelman syndrome and 15q-linked autism, there is increased interest in studying the role of UBE3A in neural functions. Surprisingly little is known about UBE3A, but this is beginning to change.
We know that UBE3A is a ubiquitin E3 ligase that is involved in the degradation of proteins via the ubiquitin-proteasome pathway. Because point mutations that eliminate UBE3A ubiquitin ligase activity are sufficient to cause Angelman syndrome, the most likely explanation for Angelman syndrome — and for 15q-linked autism — is accumulation or enhanced degradation of UBE3A targets.
There are potentially many UBE3A targets and these may be relevant to multiple signaling pathways across different brain regions and periods of brain development. In this way, inappropriate levels of UBE3A may account for the multiple hits that are believed to underlie most cases of autism. Accordingly, a clear research goal is to identify UBE3A substrates in the brain that contribute to neural dysfunction, and the resulting cognitive and behavioral deficits.
Researchers are beginning to identify these brain-specific UBE3A targets6. Last year, Michael Greenberg's laboratory at Harvard Medical School identified two protein targets of UBE3A, called ARC and EPHEXIN-5, that affect synaptic receptors — proteins involved in neurotransmission7,8.
Combined with the subtle changes in brain morphology seen in people with Angelman syndrome and autism, these observations support the idea that both are largely disorders of the synapse, the junction between neurons9.
Postmortem studies of Angelman syndrome have revealed brain region-specific reductions in the density of dendritic spines — the sites of connections between neurons. Changes in synapse density and morphology may also be common features of autism spectrum disorders10.
Common circuits:
By identifying brain regions with impaired synapses caused by inappropriate UBE3A levels, we aim to understand how disrupted circuits contribute to both Angelman syndrome and autism spectrum disorders.
Research published in the past few years indicates that lack of the UBE3A protein prevents brain circuits from strengthening in response to experiences in the mouse sensory neocortex, a brain region involved in regulating sensory perceptions11,12. For example, in mice, UBE3A is required for ocular dominance plasticity — a well-defined model in which brain circuits are refined in response to experience during a critical period of brain development.
Changes in the ability to modify brain circuits in response to experience could underlie the sensory processing and cognitive deficits associated with Angelman syndrome. Whether excessive UBE3A, as seen in 15q-linked autism, also results in altered circuit plasticity remains to be tested. We suggest that the circuits affected in Angelman syndrome are similar to those disrupted in 15q-linked autism and perhaps other autism spectrum disorders as well.
Because Angelman syndrome and 15q-linked autism result from a clear genetic cause, these disorders are comparatively more tractable for therapeutic intervention than are other forms of autism. By studying the mechanisms of UBE3A gene imprinting and the role of UBE3A in circuit development, our goal is to help pave the way for novel therapies for both disorders.
Behavioral interventions can partially restore synapse and circuit plasticity in Angelman syndrome mice12. This suggests that the mechanisms underlying synaptic plasticity remain intact in the absence of UBE3A. If the same applies to autism, then behavioral or pharmacological therapies have the potential to restore function.
The identification of pathways relevant to synapse dysfunction in Angelman syndrome and 15q-linked autism will largely be based on the identification of brain-specific UBE3A targets. It is likely that UBE3A substrates accumulate to inappropriately high levels in Angelman syndrome but are degraded to inappropriately low levels in 15q-linked autism. Pharmacological approaches could regulate key UBE3A substrates and the pathways through which they signal.
Because UBE3A targets may be too numerous to address individually, manipulating UBE3A expression levels directly is potentially a more promising therapeutic strategy. Indeed, our laboratory, together with our collaborators Mark Zylka and Bryan Roth, has been awarded a grant from the Simons Foundation, SFARI.org's parent organization, to identify ways to manipulate UBE3A levels as a treatment for autism spectrum disorders.
Benjamin Philpot is associate professor of cell and molecular physiology at the University of North Carolina School of Medicine. Angela Mabb and Matthew Judson are postdoctoral fellows in his lab.
Original source of article: Insights for autism from Angelman syndrome
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