Gene associated with progressive deafness

A gene associated with a rare form of progressive deafness in males has been identified by an international team of researchers. The gene, PRPS1, appears to be crucial in inner ear development and maintenance. The findings are published in the 17 December online issue of the American Journal of Human Genetics.

“This discovery offers exciting therapeutic implications,” said James F. Battey, Jr, MD, PhD, director of the US National Institute on Deafness and Other Communication Disorders. “Not only does it give scientists a way to develop a targeted treatment for hearing loss in boys with this disorder, it may also open doors to the treatment of other types of deafness, including some forms of acquired hearing loss.”

The gene is associated with DFN2, a progressive form of deafness that primarily affects males. Boys with DFN2 begin to lose their hearing in both ears roughly between the ages of 5 and 15, and over the course of several decades will experience hearing loss that can range from severe to profound.

Their mothers, who carry the defective PRPS1 gene, may experience hearing loss as well, but much later in life and in a milder form. Families with DFN2 have been identified in the United States, Great Britain and China.

The researchers led by Xue Zhong Liu, MD, PhD, of the University of Miami Miller School of Medicine in the US, discovered that the PRPS1 gene encodes the enzyme phosphoribosylpyrophosphate (PRPP) synthetase 1, which produces and regulates PRPP (phospho-ribosylpyrophosphate), and appears to play a key role in inner ear development and maintenance.

The four mutations identified in the PRPS1 gene cause a decrease in the production of the PRPP synthetase 1 protein that results in defects in sensory cells (hair cells) in the inner ear, and eventually leads to progressive deafness.

• Citation: Xuezhong Liu et al, “Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic Xlinked Sensorineural Deafness, DFN2” The American Journal of Human Genetics, Volume 86, Issue 1, 65-71, 17 December 2009, doi:10.1016/j.ajhg. 2009.11.015



4 distinct subtypes shown in glioblastoma multiforme

The most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is not a single disease but appears to be four distinct molecular subtypes, according to a study by The Cancer Genome Atlas (TCGA) Research Network. The researchers of this study also found that response to aggressive chemotherapy and radiation differed by subtype.

Patients with one subtype treated with this strategy appeared to succumb to their disease at a rate approximately 50% slower than patients treated with less aggressive therapy.

This effect was seen to a lesser degree in two of the subtypes and not at all in the fourth subtype. Although the findings do not affect current clinical practice, the researchers said the results may lead to more personalised approaches to treating groups of GBM patients based on their genomic alterations.

The study, published 19 January 2010 in Cancer Cell, provides a solid framework for investigation of targeted therapies that may improve the near uniformly fatal prognosis of this cancer.

GBM is a very fast-growing type of tumour. In recent years, 3 of every 100,000 Americans have been diagnosed with GBM, representing the highest incidence rate among malignant brain tumours. Most patients with GBM die of the disease within approximately 14 months of diagnosis.

“These new findings offer critical insights into stratifying patients based on the unique molecular characteristics of their disease,” said John E. Niederhuber, MD, director of the US National Cancer Institute, which funded the research. “As we learn more and more about the genetic underpinnings of cancer, we hope to achieve a similar level of molecular understanding for all cancers and eventually to generate recipes of highly targeted therapies uniquely suited to the individual patient.”

● Citation: Verhaak RGW, Hoadley KA, et al. “Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1.” Cancer Cell, 19 Jan 2010. DOI 10.1016/j.ccr.2010.12.020.



Scientists find gene that regulates heart rhythm

A gene that regulates the rhythm of the heart is revealed in new research published in Nature Genetics. The authors of the study, from Imperial College London, say their discovery helps them understand how the body’s heartbeat is controlled and could ultimately help scientists design more targeted drugs to prevent and treat certain heart problems.

The researchers have discovered a new ion channel – a channel of specialized proteins along which the electrical signals that control the heartbeat travel around the heart – called SCN10A.

This ion channel directly influences heart rhythm disturbances and a person's risk of cardiac arrest caused by ventricular fibrillation. The mutation identified in the SCN10A gene is common and, at an individual level, has a modest effect on a person’s risk of having heart rhythm problems. Further research is needed to determine what other mutations exist in this gene, and whether these variants might have a stronger effect.

The researchers analysed the genetic make-up of almost 20,000 people to look for genetic factors influencing the heartbeat. They discovered that variation in the gene that encodes the ion channel SCN10A was associated with slow and irregular heart rhythms, including risk of ventricular fibrillation.

Professor Peter Weissberg, Medical Director at the British Heart Foundation, said: "These findings are important and exciting. By looking at how differences in our genes are linked to differences in our heartbeat, this research has discovered that a single letter change in a gene can make some people more prone to heart rhythm disturbances.

Before this, we didn't even realise that the protein produced by this gene was present in heart cells - now it looks like it could be a target for drug development to prevent life-threatening heart rhythm problems.

● Citation: JC Chambers et al. “Genetic variation in SCN10A influences cardiac conduction and risk of ventricular fibrillation” Nature Genetics 42, 149 - 152 (2010) Published online: 10 January 2010, doi:10.1038/ng.516



3 genes identified as source of stuttering

A study lead by researchers at the US National Institute on Deafness and Other Communication Disorders (NIDCD) identifies three genes as a source of stuttering in volunteers in Pakistan, the United States, and England.

It appears stuttering may be the result of a glitch in the dayto- day process by which cellular components in key regions of the brain are broken down and recycled as two of the genes have already been implicated in other rare metabolic disorders also involved in cell recycling, while mutations in a third, closely related, gene have now been shown to be associated for the first time with a disorder in humans.

“For hundreds of years, the cause of stuttering has remained a mystery for researchers and health care professionals alike, not to mention people who stutter and their families,” said James F. Battey, Jr, MD, PhD, director of the NIDCD. “This is the first study to pinpoint specific gene mutations as the potential cause of stuttering.” Stuttering tends to run in families, and researchers have long suspected a genetic component.

Previous studies of stuttering in a group of families from Pakistan had been done by Dennis Drayna, PhD, a geneticist with the NIDCD, which indicated a place on chromosome 12 that was likely to harbor a gene variant that caused this disorder. In this study Dr Drayna, lead author of the study, and his team refined the location of this place on chromosome 12.

They sequenced the genes surrounding a new marker and identified mutations in a gene known as GNPTAB in the affected family members. This gene encodes an enzyme that assists in breaking down and recycling cellular components.

They then analysed the genes of 123 Pakistani individuals who stutter – 46 from the original families and 77 who are unrelated – as well as 96 unrelated Pakistanis who don’t stutter, and who served as controls. Individuals from the United States and England also took part in the study, 270 who stutter and 276 who don’t.

The researchers found some individuals who stutter possessed the same mutation as that found in the large Pakistani family.

They also identified three other mutations in the GNPTAB gene which showed up in several unrelated individuals who stutter but not in the controls. The GNPTAB and GNPTG genes have already been tied to two serious metabolic diseases known as mucolipidosis (ML) II and III.

MLII and MLIII are part of a group of diseases called lysosomal storage disorders because improperly recycled cell components accumulate in the lysosome. Large deposits of these substances ultimately cause joint, skeletal system, heart, liver, and other health problems as well as developmental problems in the brain. They are also known to cause problems with speech.

“You might ask, why don’t people with the stuttering mutations have more serious complications? Why don’t they have an ML disease?” Dr Drayna questioned. “ML disorders are recessive. You need to have two copies of a defective gene in order to get the disease.

Nearly all of the unrelated individuals in our study who stuttered had only one copy of the mutation. Also, with stuttering, the protein is still made, but it’s not made exactly right. With ML diseases, the proteins typically aren’t made at all.

Still, there are a few complexities remaining to be understood, and we’d like to learn more about them.” The findings open new research avenues into possible treatments for stuttering.

For example, current treatment methods for some lysosomal storage disorders involve injecting manufactured enzyme into a person's bloodstream to replace the missing enzyme. The researchers wonder if enzyme replacement therapy might be a possible method for treating some types of stuttering in the future.

● Citation: D Drayna et al, Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering, NEJM, 10 February 2010 (10.1056/NEJMoa0902630)