Daily Archives: December 1, 2014

PUBLIC RELEASE DATE:

1-Dec-2014

Contact: Glenna Picton picton@bcm.edu 713-798-4710 Baylor College of Medicine @bcmhouston

HOUSTON -- (Dec. 1, 2014) - Most genes are inherited as two working copies, one from the mother and one from the father. However, in a few instances, a gene is imprinted, which means that one copy is silenced. This is called genomic imprinting. If the active copy is mutated, then disease results, even though the silenced gene copy may be normal.

Angelman syndrome, which causes learning difficulties, speech problems, seizures, jerky movements and an unusually happy disposition, results when a gene inherited from the mother in a particular area of chromosome 15 is mutated and the other copy of the gene, inherited from the father, is silenced. In a report that appears online in the journal Nature Dr. Arthur Beaudet, professor of molecular and human genetics at Baylor College of Medicine and a clinical geneticist at Texas Children's Hospital, and colleagues answer the question: "Can we turn on the activity of the paternal gene?"

Angelman syndrome occurs when an infant inherits a mutated copy of the imprinted gene UBE3A from his or her mother. He or she also has a paternal copy of the gene, but it is silenced by a long ribbon of RNA called the UBE3A anti-sense transcript. (Antisense, in this case, is complementary to the ribbon of RNA, which means it binds to it and silences any activity.)

In an earlier experiment, Dr. Ben Philpott of the University of North Carolina showed that a type of drug called a topoisomerase could activate the father's copy of the gene, but the drug itself was toxic and it did not limit activation to the Angelman gene but affected all long genes.

One of Beaudet's graduate students - Linyan Meng - was writing her dissertation on Angelman syndrome and was wrestling with this problem when a member of her dissertation committee, Dr. Thomas Cooper, professor of pathology & immunology at Baylor, said he was working with a Carlsbad, Calif.-based company called Isis Pharmaceuticals that had anti-sense oligonucleotides that could turn off the antisense transcript that silenced the paternal copy of the gene. She bred a mouse in which the antisense transcript was "knocked down" and the paternal copy of the gene turned on.

"If you blocked the antisense, you could turn on the paternal copy," said Beaudet, also the Henry and Emma Meyer Chair in Molecular Genetics at Baylor. The treatment worked both in cells in the laboratory and in the live animals. The effect of the injection of the antisense oligonucleotides lasted about 16 weeks.

"It was clear from the molecular data that we were turning on the paternal copy of the gene," said Beaudet. "It is not clear how much we are able to reverse the behavioral abnormalities."

Originally posted here:
Taking the 'mute' off silenced gene may be answer to Angelman syndrome

PUBLIC RELEASE DATE:

1-Dec-2014

Contact: David Slotnick newsmedia@mssm.edu The Mount Sinai Hospital / Mount Sinai School of Medicine @mountsinainyc

(NEW YORK - December 1, 2014) Kidneys donated by people born with a small variation in the code of a key gene may be more likely, once in the transplant recipient, to accumulate scar tissue that contributes to kidney failure, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published today in the Journal of Clinical Investigation.

If further studies prove the variation to cause fibrosis (scarring) in the kidneys of transplant recipients, researchers may be able to use it to better screen potential donors and improve transplant outcomes. Furthermore, uncovering the protein pathways that trigger kidney fibrosis may help researchers design drugs that prevent this disease process in kidney transplant recipients, and perhaps in all patients with chronic kidney disease.

"It is critically important that we identify new therapeutic targets to prevent scarring within transplanted kidneys, and our study has linked a genetic marker, and related protein pathways, to poor outcomes in kidney transplantation," said Barbara Murphy, MD, Chair, Department of Medicine, Murray M. Rosenberg Professor of Medicine (Nephrology) and Dean for Clinical Integration and Population Health at the Icahn School of Medicine at Mount Sinai. "Drug designers may soon be able to target these mechanisms."

A commonly used study type in years, the genome-wide association study (GWAS) looks at differences at many points in the genetic code to see if, across a population, any given variation in the genetic code is found more often in those with a given trait; in the case of the current study, with increased fibrosis in recipients of donated kidneys.

Even the smallest genetic variations, called single nucleotide polymorphisms (SNPs), can have a major impact on a trait by swapping just one of 3.2 billion "letters" making up the human DNA code. The current study found a statistically significant association between SNP identified as rs17319721 in the gene SHROOM3 and progressive kidney scarring (fibrosis) and function loss in a group of kidney donors, mostly of European descent. In many cases, certain SNPs will be more common in families or ethnic groups.

The kidneys filter the blood to remove extra blood sugar and waste products that trickle down the kidney tubes to become urine, while re-absorbing key nutrients. The build-up of scar tissue in these delicate structures over time interferes with proper renal function.

Chronic kidney disease already affects 10 percent of US adults and its prevalence is increasing. Along with leading to kidney failure in many cases, chronic kidney disease increases the risk of cardiovascular disease. Fibrosis in kidney tubules is a common pathogenic process for many types of chronic kidney disease, and a central part of chronic disease in donated kidneys (chronic allograft nephropathy, or CAN).

Visit link:
Genetic marker may help predict success of kidney transplants