The age at which girls reach sexual maturity is influenced by ‘imprinted’ genes, a small sub-set of genes whose activity differs depending on which parent passes on that gene, according to new research.

The findings come from an international study of more than 180,000 women involving scientists from 166 institutions worldwide, including the University of Cambridge. The researchers identified 123 genetic variations that were associated with the timing of when girls experienced their first menstrual cycle by analysing the DNA of 182,416 women of European descent from 57 studies. Six of these variants were found to be clustered within imprinted regions of the genome.

Lead author Dr John Perry at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge says: “Normally, our inherited physical characteristics reflect a roughly average combination of our parents’ genomes, but imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes. Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”

The activity of imprinted genes differs depending on which parent the gene is inherited from – some genes are only active when inherited from the mother, others are only active when inherited from the father. Both types of imprinted genes were identified as determining puberty timing in girls, indicating a possible biological conflict between the parents over their child’s rate of development. Further evidence for the parental imbalance in inheritance patterns was obtained by analysing the association between these imprinted genes and timing of puberty in a study of over 35,000 women in Iceland, for whom detailed information on their family trees were available.

This is the first time that it has been shown that imprinted genes can control rate of development after birth.

Dr Perry says: “We knew that some imprinted genes control antenatal growth and development – but there is increasing interest in the possibility that imprinted genes may also control childhood maturation and later life outcomes, including disease risks.”

Senior author and paediatrician Dr Ken Ong at the MRC Epidemiology Unit says: “There is a remarkably wide diversity in puberty timing – some girls start at age 8 and others at 13. While lifestyle factors such as nutrition and physical activity do play a role, our findings reveal a wide and complex network of genetic factors. We are studying these factors to understand how early puberty in girls is linked to higher risks of developing diabetes, heart disease and breast cancer in later life – and to hopefully one day break this link.”

Dr Anna Murray, a co-author from the University of Exeter Medical School, adds: “We found that there are hundreds of genes involved in puberty timing, including 29 involved in the production and functioning of hormones, which has increased our knowledge of the biological processes that are involved, in both girls and boys.” University of Cambridge

Use of exome sequencing improved the ability to identify the underlying gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes (enzymes that are involved in basic energy production), according to a study in the July 2 issue of JAMA.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of l in 5,000 live births. Clinically these disorders can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death. The diagnosis of mitochondrial disorders remains challenging, according to background information in the article. Examples of problems caused by mitochondrial diseases include a type of epilepsy; mitochondrial encephalopathy; lactic acidosis; and a syndrome that includes stroke-like episodes.

Robert W. Taylor, Ph.D., F.R.C.Path., of Newcastle University, Newcastle upon Tyne, U.K., and colleagues studied whether a whole-exome sequencing approach could help define the molecular basis of mitochondrial disease. Whole-exome sequencing is a complex laboratory process that determines the entire unique sequence of an organism’s exome (the collection of exons, which are relatively small lengths of a whole genome and contain instructions for the body to build proteins).

The study included 53 patients, referred to 2 national centres in the United Kingdom and Germany between 2005 and 2012, who had biochemical evidence of multiple respiratory chain complex defects. The majority (51/53 [96 percent]) of the patients presented during childhood (<15 years old) and most (66 percent) developed symptoms within the first year of life. The most frequent clinical features were muscle weakness, central neurological disease, cardiomyopathy, and abnormal liver function; a combination of these abnormalities was present in most cases. Following whole-exome sequencing, presumptive causal variants were identified in 28 patients (53 percent) and possible causal variants were identified in 4 (8 percent). Together these accounted for 32 patients (60 percent) and involved 18 different genes. Distinguishing clinical features included deafness and kidney involvement associated with one gene, and cardiomyopathy with two genes. In 20 patients with prominent heart disease, the causative mutation was detected in 80 percent, while the detection rate was much lower in patients with liver disease (33 percent). It was not possible to confidently identify the underlying genetic basis in 21 patients (40 percent). “In the pre-exome era, the systematic biochemical characterization of 53 patients with multiple respiratory chain complex defects led to detection of the underlying genetic basis in only 1 patient. The work presented herein demonstrates the effect of whole-exome sequencing in this context, which has defined the genetic etiology in 32 of 53 patients (60 percent) with a confirmed biochemical defect …,” the authors write. “Our findings contrast with large-scale candidate gene analysis using conventional and next-generation sequencing approaches, both of which had a lower diagnostic yield (10 percent-13 percent) and by definition did not discover new potential disease genes.” “Additional study is required to determine the utility of this approach compared with traditional diagnostic methods in independent patient populations,” the researchers conclude. JAMA Network

Researchers have found evidence that genetic factors may contribute to the development of language during infancy.

Scientists from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol worked with colleagues around the world to discover a significant link between genetic changes near the ROBO2 gene and the number of words spoken by children in the early stages of language development.

Children produce words at about 10 to 15 months of age and our range of vocabulary expands as we grow – from around 50 words at 15 to 18 months, 200 words at 18 to 30 months, 14,000 words at six-years-old and then over 50,000 words by the time we leave secondary school.

The researchers found the genetic link during the ages of 15 to 18 months when toddlers typically communicate with single words only before their linguistic skills advance to two-word combinations and more complex grammatical structures.

The results shed further light on a specific genetic region on chromosome 3, which has been previously implicated in dyslexia and speech-related disorders.

The ROBO2 gene contains the instructions for making the ROBO2 protein. This protein directs chemicals in brain cells and other neuronal cell formations that may help infants to develop language but also to produce sounds.

The ROBO2 protein also closely interacts with other ROBO proteins that have previously been linked to problems with reading and the storage of speech sounds.

Dr Beate St Pourcain, who jointly led the research with Professor Davey Smith at the MRC Integrative Epidemiology Unit, said: ‘This research helps us to better understand the genetic factors which may be involved in the early language development in healthy children, particularly at a time when children speak with single words only, and strengthens the link between ROBO proteins and a variety of linguistic skills in humans.”

Dr Claire Haworth, one of the lead authors, based at the University of Warwick, commented: “In this study we found that results using DNA confirm those we get from twin studies about the importance of genetic influences for language development. This is good news as it means that current DNA-based investigations can be used to detect most of the genetic factors that contribute to these early language skills.’ University of Bristol

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found.

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. ‘Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,’ Chen said.

The research behind those drugs had targeted the long-recognised feature of Alzheimer’s patients’ brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die.

‘The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,’ Chen explained.

‘We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients,’ Chen said.

He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called ‘reactive astrocytes’ in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.

Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped ‘astrocyte’ cells which, in a healthy individual, surround and support individual neurons in the brain. ‘Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,’ Chen said.

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice).

‘Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,’ Chen said.

His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Importantly, Chen said, ‘After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.’ Penn State University

Scientists at The University of Texas MD Anderson Cancer Center may have discovered why some brain cancer patients develop resistance to standard treatments including radiation and the chemotherapy agent temozolomide.

Simply put, it’s all in their DNA, and it could open up new avenues for treating certain kinds of brain cancer.

DNA, the body’s essential storehouse for genetic information. In the case of glioblastoma, the most common and aggressive type of glioma or brain cancer, it can also allow the disease to progress more quickly when it is “enhanced,” allowing damaged or mutated cancer cells to repair themselves.

“A major obstacle to effective treatment is acquired resistance to treatment,” said Wei Zhang, Ph.D., professor of Pathology. “Enhanced DNA repair can allow these cancer cells to survive, contributing to resistance and tumour recurrence. We have identified Aktr3 as having the ability to robustly stimulate glioma progression.”

Akts are proteins known as kinases that regulate cell signalling. They’re involved in many bodily processes such as cell growth, cell death and tumour growth. Akts are thought to contribute to the development and progression of many cancers including prostate, breast, liver, colorectal and others. One form of this protein, Akt3, appears to be especially prevalent in the brain.

Zhang’s findings describe his team’s study results showing how Akt3 activates key DNA repair pathways.

In Zhang’s research, he reveals that Akt3 is tied to DNA’s “repair panel,” somehow boosting activation of DNA repair proteins, leading to increased DNA repair, and subsequently to cancer treatment resistance.

“This activation led to enhanced survival of brain tumour cells following radiation or treatment with temozolomide,” said Zhang. “Our work has potentially broad application to multiple cancer types in which Akt3 is expressed. Blocking this pathway may help prevent or alleviate therapeutic resistance resulting from enhanced DNA repair.” MD Anderson Cancer Center