Although only a small proportion of stutterers are likely to have these genetic mutations, the study is the first to pinpoint specific gene mutations as a potential cause of stuttering. Recently, enzyme replacement therapy has been developed to treat lysosomal storage disorders and, if the mutations involved in stuttering also prove to involve loss of enzyme function, such treatments could eventually also be effective for this group of stutterers.
Researchers at Stanford University School of Medicine and the University of California have now suggested a possible treatment for the neurological manifestations of Down’s syndrome. The team carried out experiments in a well established mouse model of Down’s syndrome. The mice, which have three copies of a fragment of mouse chromosome 16, show abnormal responses in behavioural tests of contextual learning such as conditioned fear learning. The mice also did not build nests when placed in a strange environment, unlike wild type animals. When the team examined the mice, they found significant neurodegeneration in the locus coeruleus region of the brain – an area that also degenerates in the brains of people with Down’s syndrome. The locus coeruleus supplies the hippocampus with the neurotransmitter, norepinephrine (noradrenaline), and when the genetically engineered mice were treated with L-DOPS (L-threo-dihydroxyphenylserine), a prodrug of norepinephrine and epinephrine which can cross the blood-brain barrier, they behaved much more like normal animals in both fear conditioning tests and nest building activities. Direct examination of neurons in the hippocampus of the genetically altered mice showed that these cells responded well to norepinephrine.
Degeneration in the locus coeruleus also occurs in other dementias, including Alzheimer’s disease, and mice with three copies of the gene expressing APP had fewer neurons producing norepinephrine than those with just two copies.
The authors hope that early intervention with agents targeting the norepinephrine system could lead to improvements in cognitive function in children with Down’s syndrome. Since improvements were seen even in the presence of established neurodegeneration in the genetically engineered mice, such agents may also have a role in restoring function in older individuals with Down’s syndrome and in Alzheimer’s disease sufferers. Previous studies of drug treatments for Down’s syndrome have focused on the neurotransmitter acetylcholine, which also acts at the hippocampus. Based on the new findings, the researchers suggest that the ideal treatment approach for improving cognition in people with Down’s syndrome will likely enhance both norepinephrine and acetylcholine signalling.
The study is published in Science Translational Medicine.
SMA results when the SMN1 (survival of motor neuron 1) gene, which encodes survival of motor neuron (SMN) protein, is missing or mutated. SMN is critical to the survival and health of motor neurons. The closely related survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. Although SMN2 differs from SMN1 by only a single nucleotide, the change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. As a result, SMN2 produces less full-length mRNA and protein than SMN1.
Image: Wikipedia - André Karwath In fact not just one, but a whole bunch of them! Whilst not immediately obvious, researchers at North Carolina State and Boston universities have found them pretty useful in the study of alcohol tolerance. Recognising the difficulties of genome-wide association studies (GWAS) in humans, the team used Drosphila as a model to investigate the genetic networks underlying responses to ethanol. By comparing changes in gene expression to differences in phenotypic response, a number of genes were identified that correlated with variation in susceptibility, as well as induction of tolerance, to alcohol.
Importantly, many of the genes identified have human orthologues, enabling focused analysis of their roles in human responses to alcohol. Indeed, the team found that polymorphisms in one of these, malic enzyme-1, correlated with alcohol consumption in humans.
The study, published in the October print edition of the journal Genetics, paves the way to greater insight into the genetic factors that may predispose individuals to alcoholism. It may also reveal mechanisms for the negative side-effects of alcohol such as ‘fatty liver’, a precursor to cirrhosis.
Floppy Baby Syndrome encompasses a number of incurable genetic diseases that cause severe muscle weakness. In one form of the disease, mutations occur in the ACTA1 gene which encodes the skeletal muscle protein, alpha actin. 
Most babies born with these mutations are almost completely paralysed and die within their first year but a team of Australian scientists identified a number of less severely affected children who were found to have cardiac actin expressed abnormally in skeletal muscle. In the early foetus, cardiac actin is the most abundant form of the protein in both heart and skeletal muscle but, during development, production of skeletal actin increases until it becomes the dominant form in skeletal muscle. Although the switch occurs in all higher vertebrates, it is not clear why it occurs, or why it occurs only in skeletal muscle.
Mice lacking the ACTA1 gene die within nine days of birth but the team have now shown that if the mice are crossed with transgenic mice expressing ACTC at high levels in skeletal muscle cells the pups survive much longer. ACTC encodes the heart muscle protein, alpha cardiac actin, and almost all of the mice with this gene survived for more than three months and some for more than two years. Although their individual muscle fibres were slightly weaker, their overall muscle strength and locomotive performance were comparable with those of wild type mice. The study demonstrates that cardiac actin is sufficiently similar to skeletal actin to produce adequate muscle function and the team hope that ACTC reactivation might provide an approach for the treatment of diseases caused by ACTA1 mutations. The team are exploring the effects of existing medicines to see whether any of them can ‘switch on’ the ACTC gene in skeletal muscle.
The study is published in the Journal of Cell Biology.
Autism, the best known of the autism spectrum disorders (ASDs), is a relatively common condition affecting around 1 in 150 children in the US, with about four times more boys than girls affected. People with autism spectrum disorders struggle with social communication and interactions, and have difficulty relating to other people and their emotions. A number of factors – both genetic and environmental – have been suggested to be linked to autism and two recent studies have now provided evidence of associations with genetic variations.
In the first study, which is published in the journal Nature, variations in a region close to the genes for two neuronal cell-adhesion molecules, cadherin 9 (CDH9) and cadherin 10 (CDH10) were found to occur more frequently in children with ASDs than in unaffected children. These cadherin molecules, which are expressed on the surface of neurons, mediate calcium-dependent cell-cell adhesion and are important in shaping the physical structure of the developing brain as well as the functional connections between different areas of the brain. The researchers propose that these gene variants are new susceptibility factors for ASDs and estimate that they may contribute to up to 15% of cases.
The second study, also published in the journal Nature, identified copy number variations – deletions or duplications of DNA – in genes belonging to two biological pathways. Interestly, one pathway involved the same neuronal cell-adhesion molecule gene family that was identified in the first study, whilst the other involved genes in the ubiquitin degradation pathway. The role of ubiquitin, which tags proteins – including the neuronal cell-adhesion molecules – for proteasome-mediated degradation, presents a mechanism that links the two gene pathways. The new data support previous evidence from functional magnetic resonance imaging studies showing that children with ASDs may have reduced connectivity among neural cells, and with anatomy studies that have found abnormal development in the frontal lobes in autistic patients.
Although the new information does not fully explain why some children develop ASDs and cannot immediately be used to provide clinical treatments, it should provide ideas for further experiments that may eventually lead to strategies for the prevention or early treatment of ASDs.
