Jackson researchers find single-gene culprit for blood diseases

August 15, 2010

Courtesy: insciences.org

Bar Harbor, Maine — Jackson Laboratory Professor Luanne Peters, Ph.D., and colleagues discovered that the mouse mutant Nan, a model for severe inherited anemia, carries a single-gene mutation, but one that selectively interferes with a cascade of events critical to normal red blood cell formation.

The discovery could point the way to future treatments for beta thalassemia, sickle cell disease or other blood disorders, and appears to represent a previously unknown mechanism of inherited disease.

Peters explains that the anemic Nan is one of dozens of mouse models of blood disease that she and her laboratory have studied over the past two decades. Mary Lyon of MHC Harwell in England had published a description of the mutation in the old Mouse Newsletter in 1983, and Peters asked Lyon to send her the mouse for analysis in 1994.

Years ago the Peters lab mapped the Nan mutation and found a single amino-acid change in one of the so-called zinc fingers of EKLF, erythroid Krüppel-like factor, which orchestrates genes that control development of blood cells. Zinc fingers are protein components that turn genes on and off. Like hands reading Braille, they search out specific DNA sequences, then bind to the DNA and insert the correct “on-off” control proteins into the target site.

“It was a pretty conservative change,” Peters says. “Glutamic acid to aspartic acid, E to D, not something by itself that you’d get wildly excited about.” Even her collaborator Dr. James Bieker of New York’s Mount Sinai School of Medicine, one of the world’s leading experts in EKLF, was “underwhelmed” with this information, she notes. “So frankly, for a while we didn’t believe it was EKLF and we kept looking for a different gene.” Adding to the mystery: Knockout mouse models lacking EKLF have a different phenotype than the Nan mouse.

The breakthrough came when Peters and her Mount Sinai collaborators conducted a simple gel-shift experiment, which showed that the Nan version of EKLF failed to bind DNA normally. Notably, this failure was selective, depending on the DNA binding site.

EKLF has three zinc fingers, each of which binds to a specific base triplet in its DNA binding site. The Nanmutation is in zinc finger 2. If the DNA binding site contains a C base, the mutant Nan EKLF binds the DNA and transactivates the gene normally. If on the other hand that triplet contains a T, “it won’t work, and all is not well,” Peters says. “A subset of erythroid genes is not expressed properly.” It was the first demonstration of a sequence-selective transcription factor defect like this, and it distinguished the Nanallele of EKLF from the null allele in the knockout models.

“It was one of those voila moments,” Peters says.

In the Nan mice, embryonic globins, which are normally down-regulated, or suppressed, after birth, are highly expressed. EKLF is a major regulator of the switch to adult globin expression. “This suggests the possibility of a drug intervention that tinkers with EKLF in order to reactivate embryonic globins in patients with beta thalassemia or sickle cell disease.”

The research findings are published in the Proceedings of the National Academy of Sciences.

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.


Gene Carriers Argue against Discrimination

August 15, 2010

Courtesy: english.cri.cn

The second trial of three job applicants who were denied jobs because they carry the thalassemia gene opened on Wednesday, in what is believed to be the country’s first case of job discrimination because of the gene.

The three, surnamed Tang, Xie and Zhou, were denied civil servant jobs by Foshan human resources and social security departments last year because they were diagnosed as thalassemia gene carriers after passing written tests and interviews.

The Chancheng District Court in Foshan, Guangdong province, rejected their appeal after their first trial in early June, claiming that carrying the thalassemia gene is regarded as having a blood disease.

The Foshan Intermediate People’s Court has yet to give a verdict, but is required to do so within two months, according to Huang Yizhi, the trio’s lawyer.

The three applicants did not appear in court on Wednesday.

However, outside the court, some students held banners and slogans to protest job discrimination of thalassemia gene carriers.

“After four years of study, every student should have the same opportunity for jobs,” said a student who declined to be named.

The second trial still focuses on whether thalassemia should be known as a blood disease, according to Huang.

Under the general physical examination standard of civil servant enrollment, applicants will be denied the job if they develop anemia, a condition caused by various mineral and vitamin deficiencies. Symptoms can include fatigue, shortness of breath, dizziness and difficulty concentrating.

“It is unfair to deny them job opportunities since their physical checkup report shows they do not have a blood disease condition,” Huang said.

According to regulations, a man will be diagnosed with thalassemia if his hemoglobin (HGB) is lower than 120 g/L. “But how can they be seen as thalassemia patients? They are only carriers, with HGB higher than the minimum level,” Huang told China Daily.

Some 31 students who were diagnosed as thalassemia gene carriers were refused civil servant jobs by Foshan human resources authorities last year, according to Xie, one of the three plaintiffs.

They were asked by the Foshan personnel department to undergo a physical examination after they passed tests and interviews last April.

Xie also did not pass the physical tests because he is a carrier of the thalassemia gene.

“But the relevant regulation for civil servant jobs does not specify that thalassemia gene carriers cannot pass the physical test,” Xie had said in an earlier interview.

Of the 31 applicants who were denied civil servant jobs, 27 are natives of Guangdong province, which is one of the provinces with the highest rates of thalassemia.

In Guangdong, one in nine people, or about 12 percent of its population, have developed thalassemia, a form of chronic anemia, according to the Guangzhou-based Southern Hospital.

“Thalassemia gene carriers with light symptoms usually do not develop physical signs. In reality, they are no different from others in terms of working and living,” said Li Chunfu, a doctor with the hospital.


Gene therapy breakthrough heralds treatment for beta-thalassemia

July 14, 2010

Courtesy: eurekalert.org

Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (ß-globin) in patients’ blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients.

The disorder β-thalassemia, also known as Cooley’s anemia, is caused when a patient cannot produce enough of the ß-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of ß-globin causes life threatening anemia, leading to severe damage of the body’s major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations.

“Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients,” said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. “Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder.”

Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient’s bone marrow. The team developed a tool to deliver the correct gene for ß-globin into these harvested cells, a viral vector they called GLOBE.

The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.

This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research

“This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish,” said Williams. “Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward.” As the Milan based team can now correct the defective production of beta-globin in patients’ blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.

Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients” concluded Ferrari. “We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector.”


Arresting spread of thalassemia

May 15, 2010

Courtesy by: thenews.com.pk

For the first time religious scholars, politicians from the ruling alliance, as well as the Speaker of the Sindh assembly, Shehla Raza, joined doctors for the prevention of thalassemia and demanded that legislation be made to take the blood test of couples before they are married.

At a press conference held by the Husaini Blood Bank on Wednesday at the Karachi Press Club, the Naib-Amir of the Jamat-e-Islami (JI), Sindh, Dr Arif Alvi, along with Aslam Ghauri, representative of the Jamiat Ulema-e-Islam (JUI) supported the demand made by the members of the blood bank and said that they would co-operate in whatever way they could.

Speaker Sindh Assembly Shehla Raza said that making a legislation wouldn’t be enough as the efficacy of law in implementing the legislation was also necessary.

Thalassemia is basically a genetic blood disease which is transferred to the children through their parents. “Thalassemia patients lead a normal life,” said Asad Ali, Chief Executive Officer at the Husaini Blood Bank, “but the problem occurs when two thalassemia minors get married which transmits the disease in their children and makes them a thalassemia major, which is far more severe.”

He said that that at present, out of the 160 million population of Pakistan, 1 million ere patients of thalassemia minor whereas 6,000 newborns every year were diagnosed with thalassemia major, which is a major cause for concern. Apart from that he said that the reason this disease is spreading so fast is that not many people are aware of its symptoms. Moreover, he said that those infected with thalassemia major need frequent blood transfusions, said Asad.

“We need 7,660 blood bags daily but unfortunately this enormous demand is not met the way it should be,” said Asad. He said that it had been proved in research that donating blood once a year protected one from cardiac diseases. The speakers stressed that legislation in this regard will help in control thalassemia.


Early passing of pre-marriage mandatory Thalassemia testing law demanded

May 15, 2010

Courtesy by: allvoices.com

Karachi: Over 11.6 million people have Thalassemia Minor in Pakistan while the country houses over 100,000 Thalassemia Major, a life-threatening disorder of the blood that is completely hereditary, the journalists were informed at Karachi Press Club at a press briefing by head of a major Blood Bank demanding early legislation of law to make pre-marriage Thalassemia testing to help reduce the fatal disease.

This was stated by the Chief Executive Officer of one of the biggest and most trusted Husaini Blood Bank, Asad Ali. Flanked by Deputy Speaker of Sindh Assembly Ms. Shahla Raza; provincial Minister for Jails Haji Muzaffar Shijra; provincial Labor Minister Ameer Nawab; central leader of Pakistan Muslim League (Nawaz) Syed Hafeezuddin; Naib Ameer Jamaat-e-Islami Meraj-ul-Huda, Secretary General of Pakistan Tehreek-e-Insaf and leader of Jamiat Ulema-e-Islam Rahman Syed Mumtaz Haider, said that despite the unanimous passage of the resolution moved by Haji Muzaffar Shijra the law to make pre-marriage Thalassemia testing was not yet passed in to a law to help bring down incidence of Thalassemia Major. “While Thalassemia Minor is common and those who have it live a normal life the probability of having this totally hereditary disease shifted to children of couples having it is resulting in pushing Thalassemia Major in the country.”

The journalists were informed that in many countries in Pakistan’s neighborhood like India, Saudi Arabia and Iran have made legislation that makes pre-marriage Thalassemia testing mandatory to help reduce Thalassemia Major incidence. However, the failure to make law has pushed Thalassemia incidence to dangaerous levels that undermines the very health of the nation.

The speakers said that if an adult Pakistani make a habit of donating just one bottle of blood a year it would help totally eradicate the acute shortage of blood in the country which stands at around 7,600 bottles a day. The journalists were also informed that each year around 6,000 babies are born in the country with Thalassemia Major and they need around 25-30 bottles of blood each year to keep alive.

The speakers also demanded that a column should be added in the Nikahnama (marriage registration certificate) to certify if a bride or a groom has Thalassemia Minor because marriage of Thalessemiazed parents almost certainly mean that one of the four children born to them would have Thalassemia Major, two from Thalassemia Minor and that only one could be a normal child.

The speakers requested the media representatives to help create the much needed awareness to understand the harming consequences of marriage of Thalassemia Minor because it poses grave risks to their children.

The press briefing coincided with the World Thalassemia Day which is celebrated on May 8 every year.


Pre-Implantation Genetic Diagnosis (PGD) in Fertility Treatments

May 15, 2010

Courtesy by: tmdcelebritynew.com

For couples undergoing in vitro fertilization (IVF), pre-implantation genetic diagnosis (PGD) is a procedure undertaken to screen the embryos for a host of genetic diseases and disorders to ensure the delivery of a healthy baby. PGD helps physicians to identify some genetic defects within the embryo, prior to implantation, before the pregnancy is established. The couple can then decide whether or not they want to continue with the pregnancy. The procedure was first conducted in 1988 and since then this technology is increasingly being used in fertility clinics in the United States.

PGD is normally recommended for couples where one or both of the parents are a known carrier of a genetic disease such as hemophilia. The procedure involves the removal of one or two cells from an embryo which are then screened for genetic abnormalities. PGD identifies the embryos with chromosome abnormalities, thereby avoiding their transfer during an in vitro fertilization procedure. The analysis helps to detect certain inherited or chromosomal diseases such as Down syndrome, Thalassemia, cystic fibrosis, hemophilia A, Tay-Sachs disease, and Turner syndrome among others, prior to implantation.

Most fertility clinics offer PGD in select cases such as:

Women over the age of 35 who have had miscarriages or failed attempts at becoming pregnant through IVF Women who have repeated pregnancy loss due to genetic disorders or who already have one child with a genetic problem Any couple who have been unable to become pregnant through multiple IVF cycles Couples who wish to identify a tissue match for a sick sibling who can be cured with transplanted cells

For couples who are at risk of passing on serious inheritable genetic diseases to their offspring, a diagnosis before embarking on a pregnancy is preferable to medically invasive, emotionally demanding prenatal diagnostic techniques. However couples with genetic disorders should receive adequate counseling about the risks of misdiagnosis and the possibility of no diagnosis before going in for PGD.

East Bay Fertility Center California, offers a wide range of infertility treatments along with expert medical counseling to couples facing difficulty in conceiving. Under the guidance of Dr. Ellen U. Snowden, Medical Director and Reproductive Endocrinologist, medical staff at East Bay provides dedicated treatment for infertility and reproductive endocrine issues.

At the center, PGD is offered as an option to couples who are at high risk of passing on a genetic disease to their children. The Center’s IVF experience and access to advanced genetic testing and counseling holds the promise of increasing the probability of a successful pregnancy outcome from an in vitro fertilization procedure and reducing the incidence of genetic disease. The use of this advanced genetic testing procedure allows only normal embryos to be transferred back into the uterus, providing a much better chance of achieving a full-term pregnancy with chromosomally healthy embryos.


Newborn Genetic Screening

May 15, 2010

Courtesy by: wcbstv.com

There is nothing more important to parents than their child’s health, but sometimes a child who looks healthy may not be.

However, there’s one test that can find illnesses hiding in plain sight, and even save your child’s life.

James Stamateris is like any 12-year-old baseball enthusiast, but he has a serious blood disorder called thalassemia major. The life-threatening illness can be picked up at birth, but in James’ case, it wasn’t.

“My doctor, I assumed, did the appropriate test, and genetic testing wasn’t offered at the time,” mother Amy Celento said.

The condition was diagnosed almost by accident by a routine blood test when he was a year old. Now, James is treated with blood transfusions every three weeks. The treatment immediately boosted his energy and personality.

“His caregiver at daycare, the first time he had a transfusion, they said, ‘oh my gosh, James is playing with everyone,'” Amy Celento said.

Now, most children with conditions like thalassemia major are diagnosed within days after birth by automatic genetic screening, done by a quick heel prick and a drop of blood. Most states test for more than 30 different disorders.

“These disorders are predominately ones that the child appears perfectly well,” Dr. Patricia Giardina, of New York Presbyterian Weill-Cornell, said. “Even the pregnancy would have gone perfectly normally, but lo and behold, the child might have a rare disorder.”

Thanks to newborn screening tests, nearly 12,000 babies each year are diagnosed with serious or life-threatening disorders, and the conditions are picked up before the symptoms even start.

“Early detection can oftentimes lesson the complications or symptoms of the disease, and perhaps even prevent complications from occurring,” Dr. Giardina said.

A growing number of parents are opting out of the testing over confidentiality concerns, but experts say there’s no reason for worry.

“Confidentiality is something that we highly respect in medicine, and we’re very cautious about preventing information from being released without the families’ permission, “Dr. Giardina said.

James Stamateris’ mother says the benefits far outweigh the risks.

“I would say do it,” Celento said. “If it’s an option, then it’s being offered to you. Do it.”

In New York State, genetic screening is done automatically, unless a parent chooses to opt out.

The information is kept under lock and key at the State Department of Health. Parents can request for their children’s records to be returned to them at any time.

More than four million children undergo genetic testing each year.


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