Philadelphia, U.S.A – Researchers studying rare genetic disorders have uncovered insights into those diseases in biological structures that regulate chromosomes when cells divide. Focusing on the cohesin complex, a group of proteins forming a bracelet that encircles chromosome pairs, scientists have discovered mutations that disrupt cohesin, causing a recently recognized class of diseases called cohesinopathies.

“We are learning more about how these genetic abnormalities that affect cohesin play a role in human development,” said study leader Matthew A. Deardorff, M.D., Ph.D., a specialist in pediatric genetics at The Children’s Hospital of Philadelphia’s Center for Cornelia deLange Syndrome and Related Diagnoses.

The research, carried out in children, cell cultures, and zebrafish, appeared May 24 in the American Journal of Human Genetics. Deardorff’s co-study leader was Frank J. Kaiser, Ph.D., of the University of Lubeck in Germany.

The cohesin complex is already known to be involved in Cornelia deLange syndrome (CdLS), a multisystem genetic disease affecting an estimated 1 in 10,000 children. The disease has a range of severity, but classically includes mental retardation, impaired growth, heart defects, feeding problems, deformed arms and hands, and distinctive facial features.

Researchers at The Children’s Hospital of Philadelphia previously were the first to discover gene mutations that cause CdLS, including forms of the disease with mental retardation and often severe limb abnormalities. The current study identified another gene, RAD21, that when mutated, causes very mild cognitive and physical impairments.

The study team first performed a genome-wide analysis of 101 children with typical CdLS and 189 children having overlapping features of the disease. None of the children had mutations in the three genes already known to cause CdLS. They identified a six-year-old boy with a deletion in a section of chromosome 8 that contains the RAD21 gene, which was known to express a cohesin protein but not previously known to cause disease. As an infant, the boy had been diagnosed with facial features similar to those of CdLS, and subsequently experienced growth retardation, but had normal cognitive development.

The researchers then focused on three additional children with deletions in RAD21 and two children with mutations within the gene, and found a similar pattern—physical features, such as short stature and distinctive facial features, overlapping with some of those seen in cohesin disorders, but with only minor cognitive delays. “These findings suggest that children who are very mildly affected may go undiagnosed,” said Deardorff.

The research team did further studies in cell cultures and a zebrafish model to investigate molecular mechanisms involved in cohesin disorders. The cohesin complex includes four proteins that join in a bracelet-like structure that surrounds sister chromatids, the identical pairs that result from chromosome duplication prior to cell division. RAD21, the protein expressed by the gene with the same name, forms a clasp that closes the bracelet. A mutated RAD21 gene weakens that clasp, impairing cohesion’s normal abilities to repair damage to DNA.

However, Deardorff added, the lab research does not currently explain the full sequence of molecular events, and further studies will investigate knowledge gaps in the process.

As the cost of whole-genome sequencing is rapidly dropping, Deardorff expects researchers to discover additional genes involved in cohesinopathies, offering further clues to how these diseases function in human development. “For now we can expect that patients with the RAD21 mutation will be less severely affected than those with classical CdLS,” he said. “As we better understand the mechanisms of these congenital diseases, we’ll continue to seek opportunities to devise more effective treatments.”

The National Institutes of Health, the U.S.A. Cornelia deLange Syndrome Foundation, The Children’s Hospital of Philadelphia and the University of Lubeck were among the organizations supporting this study.

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The U.S. Food and Drug Administration has approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.

CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.”

The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

Kalydeco was approved ahead of the drug’s April 18, 2012, prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.

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