As more and more customers are using their mobile devices to make deposits or pay bills, the banks are looking for ways to charge them for the service.
While fees for using mobile apps may be inevitable, the banks differ only over how to levy that charge.
Some banks believe it should be a fixed cost per transaction, others believe fees should only come on products that present risks to the bank and provide unique services to the customer, such as Regions Financial for immediate funds, and Wells Fargo for emergency bill pay.
Still others ? who asked not to be identified because the strategy hasn't been announced ? have lobbied for a model resembling "Amazon Prime," where customers pay a flat fee for unlimited transactions.
Birmingham, Ala.-based Regions Financial rolled out its mobile banking app this spring with a tiered fee structure, based on when the customer needed access to funds deposited digitally. For immediate availability, which is a risk to the bank because it then doesn't have time to verify the fees, customers must pay $5, or a percentage of the deposit?whichever is higher. For access two days later, once the funds are verified, the fee is 50 cents?the same fee Minneapolis-based US Bank introduced for all mobile deposits in 2010. It was the first bank to initiate such fees.
"This is just the beginning of the creative ways banks will try to compensate in a low-rate, low-growth environment," said Todd Hagerman, senior research analyst at Sterne Agee. "They have to look for alternative ways to improve their fee income stream."
Customers like Al Falussy, a sales executive on Long Island, NY, are not happy. He is a frequent user of his mobile banking app to get balance alerts, send money to employees and family, and deposit money from places where no branches are nearby.
But if Falussy's bank of choice?JP Morgan Chase?started charging to use the app? He'd switch banks.
"They're making money on my money," Falussy said of the deposits he keeps with the bank. "So for them to actually go there would be kind of petty."
Falussy and other consumers might not like it, but fees for mobile banking are set to become the norm. Slowly but surely, banks are experimenting with ways to build charges into the apps' features and as apps get higher-tech, too, a simple convenience could become costly.
(Read More: Banks Still Raising Fees?and Hiding Them: Study)
Richard Hunt, president of the Consumer Bankers Association, said banks can't afford to give customers all services free of charge, especially because of increased regulatory and legislative pressure. For one example, "checking accounts were often provided at no cost to the customer, but there is a cost to the bank providing them." Innovation on mobile, Hunt said, will fall into that category.
(Read More: Overdraft Protection Will Cost You, But How Much?)
Dave Kaminsky, a senior analyst at Mercator Advisory Group, a research firm focused on the payments industry, explained that users perceive mobile banking's offerings as worth the cost. "Customers tend to look at remote deposit capture or expedited processing as an additional value, so they're willing to pay for it?at least for now."
Customers seem to be embracing mobile banking fees so far. US Bank, a source said, hasn't experienced many customer defections since the fee was introduced in 2010. And even though Regions has the steepest fees yet, CEO Grayson Hall said on the company's last earnings call that mobile "continues to be a rapid growth channel." Perhaps one reason is that mobile, as a platform, is still surging in growth: The number of web-savvy consumers who bank only on their app jumped 55 percent in the last year, according to digital measurement outfit comScore.
Still, customer sensitivity to fees looms large as many big banks are hesitant to be the "first mover" in the space?and potentially lose customers to their competitors. JPMorgan Chase currently offers all its mobile features for free and will continue to do so, according to a person familiar with the matter.
"Deposits will eventually move from ATMs entirely to mobile," said an executive familiar with the strategy. "You want to capture that business, not turn it away." No direct fees are levied for ATM deposits.
Wells Fargo has been the only major bank to experiment with fees thus far. The bank refuses to charge for remote check deposit, which totaled 1.4 million checks in May alone, because it considers the service basic. Instead, it has chosen to charge for what it considers to be premium mobile services, like bank-to-bank transfers and emergency bill pay.
Features like emergency bill pay and immediate availability of funds are risky for banks, since it takes time to verify that the funds exist on the end of the check writer. Because banks must pay for insurance in case the money isn't there, a fee to have the money available immediately would simply cover that insurance. For that reason, at least three big banks have lobbied regulators like the Office of the Comptroller of the Currency, according to people familiar with the talks, to discuss options to verify funds without having to charge customers.
At a time when consumers feel buried in fees by their banks, one more charge tacked on to services could prompt more consumers to follow Falussy's game plan to hang up on their bank.
Prying the lids off tiny shipping crates, opening incredibly small rusted doors, fending off hordes of action figure-sized zombies: the uses for this keychain-sized crowbar are endless. And for around $15 you can add it to your pocket toolbox and never find yourself struggling to pry open a tiny coffin again.
Available from Shapeways, the mini crowbar actually comes in your choice of various metals?from stainless steel, to bronze, to even gold?because it would be all but useless if made from brittle or flexible plastic. On the other hand, if they offered a wood option, this would make for one outstanding toothpick. [Shapeways via Fancy]
A second amyloid may play a role in Alzheimer's disease, UC Davis researchers findPublic release date: 27-Jun-2013 [ | E-mail | Share ]
Contact: Phyllis Brown phyllis.brown@ucdmc.ucdavis.edu 916-734-9023 University of California - Davis Health System
A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta ?? plaques that are associated with Alzheimer's disease, a study by researchers with the UC Davis Alzheimer's Disease Center has found.
The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.
"We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now," said UC Davis Alzheimer's Disease Center Director Charles DeCarli.
"This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease," DeCarli said. "In fact, the amylin looks like the amyloid beta protein, and they both interact. That's why we're calling it the second amyloid of Alzheimer's disease."
"Amylin deposition in the brain: A second amyloid in Alzheimer's disease?" is published online in the Annals of Neurology.
Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.
Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.
When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and ??. There are about 28 amyloidogenic proteins, each of which is associated with diseases.
The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer's disease; those with Alzheimer's disease without diabetes; and age-matched healthy individuals who served as controls.
The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer's who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.
"We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the A?, which is the suspected cause of Alzheimer's disease," said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. "It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.
"It is accumulating in the brain and we found signs that amylin is killing neurons similar to ??," he continued. "And that might be the answer to the question of 'What makes obese and type 2 diabetes patients more prone to developing dementia?'"
The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer's Disease Center.
The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer's Disease Center: 15 patients with Alzheimer's disease and type 2 diabetes; 14 Alzheimer's disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.
In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.
Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.
"If we're smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer's and dementia," Despa said.
###
Additional study authors are Kaleena Jackson, Gustavo A. Barisone, Elva Diaz and Lee-Way Jin, all of UC Davis.
The study was funded by National Science Foundation grant CBET 1133339 (F.D.); American Diabetes Association grant 1-13-IN-70 (F.D.); the University of California, Davis Alzheimer's Disease Pilot Project Program (F.D.); National Institute on Aging award P30AG010129 (C.D.); and a Vision Grant from the University of California, Davis Health System (F.D.).
The UC Davis Alzheimer's Disease Center is one of only 29 research centers designated by the National Institutes of Health's National Institute on Aging. The center's goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimer's disease. Also funded by the state of California, the center allows researchers to study the effects of the disease on a uniquely diverse population. For more information, visit alzheimer.ucdavis.edu.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
A second amyloid may play a role in Alzheimer's disease, UC Davis researchers findPublic release date: 27-Jun-2013 [ | E-mail | Share ]
Contact: Phyllis Brown phyllis.brown@ucdmc.ucdavis.edu 916-734-9023 University of California - Davis Health System
A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta ?? plaques that are associated with Alzheimer's disease, a study by researchers with the UC Davis Alzheimer's Disease Center has found.
The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.
"We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now," said UC Davis Alzheimer's Disease Center Director Charles DeCarli.
"This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease," DeCarli said. "In fact, the amylin looks like the amyloid beta protein, and they both interact. That's why we're calling it the second amyloid of Alzheimer's disease."
"Amylin deposition in the brain: A second amyloid in Alzheimer's disease?" is published online in the Annals of Neurology.
Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.
Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.
When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and ??. There are about 28 amyloidogenic proteins, each of which is associated with diseases.
The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer's disease; those with Alzheimer's disease without diabetes; and age-matched healthy individuals who served as controls.
The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer's who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.
"We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the A?, which is the suspected cause of Alzheimer's disease," said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. "It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.
"It is accumulating in the brain and we found signs that amylin is killing neurons similar to ??," he continued. "And that might be the answer to the question of 'What makes obese and type 2 diabetes patients more prone to developing dementia?'"
The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer's Disease Center.
The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer's Disease Center: 15 patients with Alzheimer's disease and type 2 diabetes; 14 Alzheimer's disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.
In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.
Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.
"If we're smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer's and dementia," Despa said.
###
Additional study authors are Kaleena Jackson, Gustavo A. Barisone, Elva Diaz and Lee-Way Jin, all of UC Davis.
The study was funded by National Science Foundation grant CBET 1133339 (F.D.); American Diabetes Association grant 1-13-IN-70 (F.D.); the University of California, Davis Alzheimer's Disease Pilot Project Program (F.D.); National Institute on Aging award P30AG010129 (C.D.); and a Vision Grant from the University of California, Davis Health System (F.D.).
The UC Davis Alzheimer's Disease Center is one of only 29 research centers designated by the National Institutes of Health's National Institute on Aging. The center's goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimer's disease. Also funded by the state of California, the center allows researchers to study the effects of the disease on a uniquely diverse population. For more information, visit alzheimer.ucdavis.edu.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
June 23, 2013 ? A major study from researchers at the La Jolla Institute for Allergy and Immunology provides new revelations about the intricate pathways involved in turning on T cells, the body's most important disease-fighting cells, and was published today in the scientific journal Nature.
The La Jolla Institute team is the first to prove that a certain type of protein, called septins, play a critical role in activating a calcium channel on the surface of the T cell. The channel is the portal through which calcium enters T cells from the blood stream, an action essential for the T cell's survival, activation, and ability to fight disease.
Patrick Hogan and Anjana Rao, Ph.D.s, are senior authors on the paper and Sonia Sharma and Ariel Quintana, Ph.D.s, are co-first authors. Drs. Sharma, Rao and Hogan are former researchers at Harvard Medical School with high-level genetics expertise who joined the La Jolla Institute in 2010. Dr. Quintana conducted advanced microscopy that was a major aspect of the study.
Dr. Hogan describes the discovery as another important step in understanding the overall functioning of T cells -- knowledge from which new, more precisely targeted drugs to treat diseases ranging from cancer to viral infections can emerge. "It's like working on an engine, you have to know what all the parts are doing to repair it," he says. "We want to understand the basic machinery inside a T cell. This will enable us to target the specific pressure points to turn up a T cell response against a tumor or virus or to turn it down in the case of autoimmune diseases."
The findings were published in a Nature paper entitled "An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry."
"We have found that the septin protein is a very strong regulator of the calcium response, which is essential for activating immune cells," says Dr. Sharma, who was recently appointed to a faculty position, and now leads her own independent laboratory at the La Jolla Institute, in addition to serving as scientific director of the newly established RNAi screening center.
Dr. Hogan says the discovery took the research team by surprise. "We knew septins existed in the cellular plasma (surface) membrane, but we didn't know they had anything to do with calcium signaling," he says. Septins are known to build scaffolding to provide structural support during cell division.
This finding builds on Dr. Rao and Dr. Hogan's groundbreaking discovery in 2006 showing that the protein ORAI1 forms the pore of the calcium channel. The channel's entryway had been one of the most sought after mysteries in biomedical science because it is the gateway to T cell functioning and, consequently, to better understanding how the body uses these cells to fight disease.
To the research team's surprise, the septins were forming a ring around the calcium channel. "We aren't sure why, but we theorize that the septins are rearranging the cellular membrane's structure to "corral" the key proteins STIM and ORAI1, and maybe other factors needed for the calcium channel to operate," says Dr. Hogan.
Dr. Sharma adds that, "essentially we believe the septins are choreographing the interaction of these two proteins that are important in instigating the immune response." Without the septins' involvement, T cell activation does not occur.
In the study, the researchers devised a simple visual readout of activity in a main pathway responsible for activation of T cells -- the same pathway that is targeted by the immunosuppressive drug cyclosporin A that is used clinically -- and looked for impairment of the activity when individual genes were, in effect, deleted. After sorting through the roughly 20,000 human genes, they turned up 887 gene "hits," says Dr. Hogan.
With further experiments, they should be able to classify those hits into genes that affect the calcium channel itself and genes that act later in the pathway. "We are hopeful that one or more of these genes can be used as a clinical target for new drugs to treat transplant rejection and immune diseases, some of the same indications now treated with cyclosporine A," adds Dr. Hogan. He believes that a medication aimed at an early step of calcium entry through the ORAI channel could be more effective and have fewer side effects than cyclosporin A, which targets a later step in the pathway and can cause complications such as kidney disease.
June 13, 2013 ? Researchers at Rice University have come up with a new way to boost the efficiency of the ubiquitous lithium ion (LI) battery by employing ribbons of graphene that start as carbon nanotubes.
Proof-of-concept anodes -- the part of the battery that stores lithium ions -- built with graphene nanoribbons (GNRs) and tin oxide showed an initial capacity better than the theoretical capacity of tin oxide alone, according to Rice chemist James Tour. After 50 charge-discharge cycles, the test units retained a capacity that was still more than double that of the graphite currently used for LI battery anodes.
The research appeared this week in the American Chemical Society journal ACS Nano??.
Better batteries are greatly desired by everyone who carries a cellphone or computer or drives an electric car. The Rice team sees the potential for GNRs to contribute to their development.
Tour and his colleagues developed a method for unzipping nanotubes into GNRs, revealed in a 2009 cover story in Nature. Since then, the researchers have figured out how to make graphene nanoribbons in bulk and are moving toward commercial applications. One area ripe for improvement is the humble battery. In an increasingly mobile world, battery capacity is becoming a bottleneck that generally limits devices to less than a day's worth of use.
In the new experiments, the Rice lab mixed graphene nanoribbons and tin oxide particles about 10 nanometers wide in a slurry with a cellulose gum binder and a bit of water, spread it on a current collector and encased it in a button-style battery. GNRs are a single atom thick and thousands of times longer than they are wide. The GNRs not only separate and support the tin oxide but also help deliver lithium ions to the nanoparticles.
Lab tests showed initial charge capacities of more than 1,520 milliamp hours per gram (mAh/g). Over repeated charge-discharge cycles, the material settled into a solid 825 mAh/g. "It took about two months to go through 50 cycles," said lead author Jian Lin, a postdoctoral researcher at Rice, who believes it could handle many more without losing significant capacity.
GNRs could also help overcome a prime difficulty with LI battery development. Lithium ions tend to expand the material they inhabit, and the material contracts when they're pulled away. Over time, materials like silicon, which shows extraordinary capacity for lithium, break down and lose their ability to store ions. Other labs at Rice have made breakthroughs that help solve the expansion problem by breaking treated silicon into a powder, achieving great capacity and many cycles.
GNRs take a different approach by giving batteries a degree of flexibility, Tour said. "Graphene nanoribbons make a terrific framework that keeps the tin oxide nanoparticles dispersed and keeps them from fragmenting during cycling," he said. "Since the tin oxide particles are only a few nanometers in size and permitted to remain that way by being dispersed on GNR surfaces, the volume changes in the nanoparticles are not dramatic. GNRs also provide a lightweight, conductive framework, with their high aspect ratios and extreme thinness."
The researchers pointed out the work is a "starting point for exploring the composites made from GNRs and other transition metal oxides for lithium storage applications." Lin said the lab plans to build batteries with other metallic nanoparticles to test their cycling and storage capacities.
Co-authors of the paper are Rice graduate students Zhiwei Peng, Changsheng Xiang, Gedeng Ruan and Zheng Yan and Douglas Natelson, a Rice professor of physics and astronomy and of electrical and computer engineering. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of mechanical engineering and materials science and of computer science at Rice.
Boeing, the Air Force Office of Scientific Research, Sandia National Laboratory and the Office of Naval Research supported the research.
While everyone's skeptical about how and why so many tech companies are involved with PRISM, the New York Times has run a heartening piece which describes how Yahoo fought hard?but ultimately failed?to avoid joining the initiative.
LONDON (AP) ? An influential committee of British lawmakers accused search giant Google of dodging its taxes on Thursday, issuing a scathing report that said the U.S. Internet company took on highly contrived arrangements serving no purpose other than to avoid paying its fair share.
The report came after testimony by Google Vice President Matt Brittin, who tried to persuade members of parliament's Public Accounts Committee that his company was transparent and fair. Committee chair Margaret Hodge rejected arguments that Google's advertising sales take place in Ireland and not the U.K.
"Google brazenly argued before this committee that its tax arrangements in the U.K. are defensible and lawful," she wrote, adding that the "argument is deeply unconvincing and has been undermined by information from whistleblowers, including ex-employees of Google, who told us that U.K.-based staff are engaged in selling."
Hodge said the government needs to act to shut down loopholes.
"The company's highly contrived tax arrangement has no purpose other than to enable the company to avoid U.K. corporation tax," she said.
Google countered on Thursday that while it welcomed the call to make the system simpler and more transparent, the company was honoring the law.
"As we've always said, Google complies with all the tax rules in the U.K., and it is the politicians who make those rules," the company said in a statement. "It's clear from this report that the Public Accounts Committee wants to see international companies paying more tax where their customers are located, but that's not how the rules operate today."
Britain is in tough economic times, struggling with austerity measures that have led to cuts in welfare programs, public-sector jobs and government spending.
Like several other multinational corporations, including Amazon, Facebook and Starbucks, Google's complex corporate structures and disproportionately low tax bills have drawn the ire of a public facing one of the worst economic crises since the Great Depression.
Google has paid less than 0.1 percent of its billions in U.K. revenue back to the government in tax. In the first quarter of this year, it made $1.3 billion in revenue from the U.K., according to a Google release. The company argues that the overwhelming majority of sales actually occur at the company's European head office in Dublin.
The location is important. In Ireland, the corporate tax rate is a bargain-basement 12.5 percent.
An investigation by the Reuters news agency cast doubt on those claims, and the committee asked to speak to Brittin for a second time.
Brittin acknowledged that Google employed "people with sales skills," but insisted that those doing the sales are in Ireland.
Hodge rejected the characterization.
"Google's reputation has been damaged by these revelations of aggressive tax avoidance," she said. "That damage will not be repaired until the company arranges to pay its fair share of tax in the country where it earns the profits from the business it conducts."
June 14, 2013 ? By identifying a protein that acts as a genetic modifier, scientists at Cold Spring Harbor Laboratory (CSHL) have solved the mystery of why some infants are born with a grave syndrome consisting of cleft palate and major deformities of the skin and limbs, while other infants bearing the same predisposing genetic mutation bear little or no sign of the illness, called EEC.
EEC stands for "Ectodactyly, Ectodermal dysplasia, Clefting syndrome." It is rare in its full-blown form, although individual aspects of the associated pathology, such as cleft palate, are more common.
EEC has a known genetic culprit, a single-"letter" DNA mutation in a gene called p63. This error causes a mutation in the p63 protein that the gene encodes. EEC is autosomal dominant, meaning that only one parent needs to contribute the defective copy of the gene for a child to develop the illness. When one parent carries the mutant gene, each child has a 50% chance of having EEC.
"But the big question is why some children with the mutation have severe birth defects, while others -- in some cases, siblings of those affected -- who bear the same p63 mutation, are mostly or entirely symptom-free," says Professor Alea Mills, Ph.D., the CSHL geneticist who led the team that has just solved this mystery.
A complex series of genetic experiments directed by Mills reveals that the presence or absence of one variant type of the p63 protein, called TAp63, determines whether or not a child with the p63 mutation will in fact develop EEC pathology. TAp63 normally protects from the birth defects, and if it is not present, pathology is certain to occur, the team's experiments showed.
Solving the mystery of variable pathology
In 1999, Mills made the first genetic "knock-out" model for p63, in mice, putting the p63 gene on the map. Mice completely lacking the p63 gene were born with birth defects similar to the severest symptoms that characterize EEC in humans. Now, with a grant from The March of Dimes Foundation, Mills' team is the first to make a "knock-in" mouse model of EEC in which they replaced the normal p63 gene with a version bearing the single-letter mutation that causes EEC in people.
"We've made the very first mouse model of human EEC syndrome," notes Emma Vernersson Lindahl, Ph.D., a postdoctoral researcher and lead author of a paper appearing today in the American Journal of Medical Genetics that announces the team's results. "These mice, like babies born with EEC, showed a range of birth defects, fully recapitulating the range of defects that one sees in the human syndrome," she says.
To solve the mystery of variable pathology, the CSHL team tested the idea that the p63 protein itself controlled or "modified" EEC's manifestation in different individuals. The scenario they tested and which proved successful was this: mice with the EEC-causing p63 mutation were crossed to mice engineered to lack TAp63, one of the two major classes of p63 proteins. Those with both genetic changes consistently had features of EEC.
Most genes generate instructions for manufacturing proteins; precisely how the gene is turned on or its message edited affects which versions of structurally distinct proteins are manufactured. All healthy people generate both major classes of p63 proteins. TAp63 proved to be the class of p63 protein that modifies EEC features. Mice lacking TAp63 did not have any pathology, which means that TAp63 loss alone is not responsible for the syndrome. But when mice lacking TAp63 also possess the EEC-causing p63 gene mutation, pathology always occurs.
This work suggests that levels of the TAp63 protein determine whether children that have inherited one copy of the EEC-causing mutation from one of their parents are born with birth defects. Mills speculates that when levels of TAp63 drop beneath a certain threshold, it is no longer protective, opening the way to pathology.
"The only way you can have the EEC mutation and be normal, or have slight symptoms of the illness such as a bit of webbing between two toes, is to have robust amounts of TAp63 protein in cells when and where it is needed, during development," says Mills.
She hopes that her team's discovery that TAp63 affects the presence of birth defects will encourage doctors treating children with EEC to compare those only mildly affected with siblings or other children who have a severe form of the disease. "It will be important to sequence DNA from these children and compare the results. What's different? If we find differences, we have nailed it. If we find that ???the sequences are exactly the same, then we might look at several factors regulating gene expression for evidence of how TAp63 is expressed differently in each group."
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Public release date: 27-Jun-2013
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