French scientists have discovered that supposedly rare mutations in the mitochondria, the ‘power plants’ of human cells responsible for creating energy, account for more than 7% of patients with a mitochondrial disease manifesting itself as a respiratory deficiency. Their data emphasise the need for comprehensive analysis of all the mitochondrial DNA (mtDNA) in patients suspected as having a mitochondrial disease, and this should include children, a researcher will tell the annual conference of the European Society of Human Genetics.
Dr. Sylvie Bannwarth and Professor Véronique Paquis, from the Hôpital Archet 2, Nice, France, together with colleagues from the ten diagnostic centres that make up the French Mitochondrial Disease Network, investigated 743 patients who were suspected of having a respiratory chain disorder caused by defective mitochondria, but who did not carry a common mtDNA mutation. Mitochondrial diseases, which can be very severe, are estimated to affect one child in every 5000, and are usually untreatable. However, prompt diagnosis can help clinicians to prescribe treatment to alleviate secondary symptoms.

‘We examined the relationship between clinical presentation of disease, age at onset, and the localisations of mutations. Our results showed that, in the French population, clinical presentations that are not associated with common mtDA mutations begin mainly before adulthood, and that neuromuscular problems are the most common manifestation of such mutations’, says Dr. Bannwarth.

‘We found that early onset disease was significantly associated with mutations in genes that code for proteins, while late onset disorder were associated with mutations in tRNA genes, and that two genes represent ‘hotspots’ for disease-causing mutations. Knowing the prevalence of these rare mutations is essential if we are to be able to improve the diagnosis of these diseases.’

There are very many mitochondrial diseases, and they manifest themselves in a large number of different ways. They can involve muscle weakness, neurological disease, respiratory, gastrointestinal and cardiac problems, and strokes. Many are degenerative, while some are relatively static.

One of the two techniques used for screening the entirety of an individual’s mtDNA was developed by Dr. Bannwarth. The use of such techniques can aid not just in diagnosis, but also in genetic counselling and prenatal diagnosis for mitochondrial disease. Up to now the study of mtDNA mutations has usually been restricted to the detection of deletions and a few common mutations, but without any data about the prevalence of rare mutations and their associated phenotypes (characteristics or traits).

‘With the advent of Next Generation Sequencing techniques, screening all mtDNA is now feasible, and this means that we can detect both common and rare mutations as well as deletions. For example, in the patients we studied we found that Leigh syndrome – a rare disorder that affects the central nervous system – was found in 41% of patients with rare mtDNA mutations. Had we not screened all of the mtDNA, including the rare mutations, we would not have known this’, says Dr. Bannwarth. ‘This is clearly a big aid to accurate diagnosis and we hope that our results will underline the importance of comprehensive mtDNA screening.’ EurekAlert

Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.
The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).
‘We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes,’ says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. ‘Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.’ Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. ‘These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.’ Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, ‘Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.’ Massachusetts General Hospital

A new understanding of the genetic process that can lead to cervical cancer may help improve diagnosis of potentially dangerous lesions for some women, and also raises a warning flag about the use of anti-viral therapies in certain cases – suggesting they could actually trigger the cancer they are trying to cure.

The analysis provides a clearer picture of the chromosomal and genetic changes that take place as the human papillomavirus sometimes leads to chronic infection and, in less than 1 percent of cases, to cervical cancer. It is the first to identify specific genes that are keys to this process.

Researchers say they want to emphasise, however, that the HPV vaccine commonly used by millions of women around the world is perfectly safe if done prior to infection with the virus. The concerns raised by this study relate only to viral therapies or possible use of a therapeutic vaccine after the virus has already been integrated into human cells.

‘It’s been known for decades that only women with prior infection with HPV get cervical cancer,’ said Andrey Morgun, an assistant professor and a leader of the study in the OSU College of Pharmacy. ‘In about 90 percent of cases it’s naturally eliminated, often without any symptoms. But in a small fraction of cases it can eventually lead to cancer, in ways that have not been fully understood.’

These findings by researchers from Oregon State University and a number of other universities or agencies in the United States, Norway and Brazil. Collaborators at OSU included Natalia Shulzhenko, an assistant professor in the OSU College of Veterinary Medicine.

The study found that some pre-cancerous lesions can acquire a higher level of chromosomal imbalances in just a small number of cells. These new features appear to do two things at the same time – finally eliminate the lingering virus that may have been present for many years, and set the stage for the beginning of invasive cancer.

So long as the virus is not eliminated, it helps to keep under control viral oncogenes that have been integrated into the patient’s genome, researchers said.

‘Some of what’s taking place here was surprising,’ Morgun said. ‘But with continued work it should help us improve diagnosis and early monitoring, to tell which lesions may turn into cancer and which will not.’

The study also concludes it could be dangerous to use antiviral treatments or therapeutic vaccines with women whose lesions already show signs of HPV integration.

This may help explain why use of the antiviral drug interferon had inconclusive results in the past, in some studies of its value in treating cervical cancer. Patients with existing HPV lesions may wish to discuss findings of this study with their physicians before starting such treatments, researchers said.

Other researchers using a similar analytical approach also found key driver genes in melanoma, according to the report. This approach may have value in identifying genomic changes that are relevant to a range of malignant tumors, scientists said. Oregon State University

Researchers at Case Western Reserve University have found that a single gene poses a double threat to disease: Not only does it inhibit the growth and spread of breast tumours, but it also makes hearts healthier.

In 2012, medical school researchers discovered the suppressive effects of the gene HEXIM1 on breast cancer in mouse models. Now they have demonstrated that it also enhances the number and density of blood vessels in the heart – a sure sign of cardiac fitness.

Scientists re-expressed the HEXIM1 gene in the adult mouse heart and found that the hearts grew heavier and larger without exercise. In addition, the animals’ resting heart rates decreased. The lowered heart rate indicates improved efficiency, and is supported by their finding that transgenic hearts are pumping more blood per beat. The team also discovered that untrained transgenic mice ran twice as long as those without any genetic modification.

‘Our promising discovery reveals the potential for HEXIM1 to kill two birds with one stone – potentially circumventing heart disease as well as cancer, the country’s leading causes of death,’ said Monica Montano, PhD, associate professor of pharmacology, member of the Case Comprehensive Cancer Center, who created the mice for the heart and breast cancer research and one of the lead researchers.

Hypertension and subsequent heart failure are characterised by a mismatch between the heart muscles’ need for oxygen and nutrients and blood vessels’ inability to deliver either at the rate required. This deficit leads to an enlarged heart that, in turn, often ultimately weakens and stops. The researchers showed that increasing blood vessel growth through the artificial enhancement of HEXIM1 levels improved overall function – HEXIM1 may be a possible therapeutic target for heart disease.

The study is the sixth from the team of Dr. Montano and Michiko Watanabe, PhD, professor of paediatrics, genetics, and anatomy at Case Western Reserve School of Medicine and director of Pediatric Cardiology Fellowship Research at Rainbow Babies and Children’s Hospital.
‘Our Cleveland-based collaborative research teams revealed that increasing HEXIM1 levels brought normal functioning hearts up to an athletic level, which could perhaps stand up to the physical insults of various cardiovascular diseases,’ Watanabe said.

The results build on the team’s findings last year that showed increased levels of HEXIM1 suppressed the growth of breast cancer tumours. Using a well-known mouse model of breast cancer metastasis, researchers induced the gene’s expression by locally delivering a drug, hexamethylene-bisacetamide using an FDA-approved polymer. The strategy increased local HEXIM1 levels and inhibited the spread of breast cancer. The team is currently making a more potent version of the drug and intends to move to clinical trials within a few years. Case Western Reserve University School of Medicine

Chlamydia trachomatis is a human pathogen that is the leading cause of bacterial sexually transmitted disease worldwide with more than 90 million new cases of genital infections occurring each year. About 70 percent of women infected with Chlamydia remain asymptomatic and these bacteria can establish chronic infections for months, or even years. Even when it causes no symptoms, Chlamydia can damage a woman’s reproductive organs. In addition, standard antibacterial drugs are proving increasingly ineffective in complete eradication, as Chlamydia goes in to persistent mode, leading to asymptomatic chronic infection. Researchers at the Max Planck Institute for Infection Biology in Berlin (MPIIB) now show that Chlamydia infections can cause mutations in the host DNA by overriding the normal mechanisms by which their host prevents unregulated growth of genetically damaged cells that pave the way for the development of cancer.
Owing to their intracellular lifestyle Chlamydia depend on various host cell functions for their survival. Chlamydia manipulates the host cell mechanism to favour its growth, however the consequences of such alterations on the fate of host cells remains enigmatic. Even more worrying is mounting epidemiological evidence which links Chlamydia infections with the development of cervical and ovarian cancer. Cindrilla Chumduri, Rajendra Kumar Gurumurthy and Thomas F. Meyer, researchers at the Max Planck Institute for Infection Biology in Berlin, have now discovered that Chlamydia induces long-lasting effects on the genome and epi-genome of their host cells. Such changes are increasingly implicated in the development of a range of cancers.

The team found increased levels of DNA breaks in Chlamydia-infected cells. In normal cells, depending on the extent of damage, cells either ‘commit suicide’ or activate repair by special protein complexes in a process called the DNA Damage Response, which reseals the broken strands of DNA and makes sure the sequence of the genetic code has not been changed. Crucially, in Chlamydia-infected cells the DNA Damage Response was impaired, leading to an error-prone repair of the DNA breaks- a potential cause of mutations. Strikingly, despite the presence of extensive DNA damage, Chlamydia infected cells continued to proliferate, facilitated by additional pro-survival signals activated in the host cells by Chlamydia. The flip-side of this forced survival of damaged cells is an increased tendency to evade the normal mechanisms that eliminate cells carrying mutations that could lead to cancer. The team believe that this could be the first step on the path to carcinogenesis of the infected cells, due to uncontrolled cell growth in the presence of accumulating DNA damage – the hallmark of cancer.

The identification of infections as the origin of human cancers is important since it would allow early prevention of cancerogenesis by means of vaccination or antibiotic treatment. Such preventive strategies are currently successfully pursued against the cancer-inducing agents Human Papiloma Virus (HPV) and Helicobacter pylori, the etiological agents of cervical and gastric cancer, respectively. However, many infection-based cancer etiologies have not been firmly established and therefore cancer treatment is usually restricted to patients at an advanced stage and with an established cancer diagnosis. The department of Professor Meyer at MPIIB therefore vigorously pursues several lines of research to unequivocally assess the linkage between bacterial infections and cancer, apart from the well-known carcinogenic role of H. pylori. The current paper by Chumduri et al. constitutes one important mosaic piece, corroborating a potential link between female ascending Chlamydia infections and ovarian cancer in particular. Max Planck Society