Genetic Link to Stuttering

stutter
Image: Flickr - Versionz
Stuttering or stammering affects people of all ages and races and most often starts between the ages of two and five, when children start to develop language skills. Although most children outgrow stuttering, about one percent of adults continue to stutter. The underlying causes are not well understood but stressful situations can make stuttering more severe and, especially in the past, the condition was believed to have a social or emotional component. It has now been recognised that developmental stuttering runs in families and a section of chromosome 12 has been linked to stuttering in a group of Pakistani families. In a study published in the New England Journal of Medicine, researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD) have now refined the location on chromosome 12 to mutations in three genes, GNPTAB, GNPTG and NAGPA, which encode proteins involved in lysosomal recycling of unwanted cellular components. Mutations in two of these genes had previously been linked with rare, and often fatal, lysosomal storage disorders.

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.

Norepinephrine Boosts Memory in Down’s Syndrome Model

Image: Wikimedia Commons
Image: Wikimedia Commons
Down’s syndrome is a chromosomal disorder caused by the presence of all (trisomy 21) or part of an extra copy of chromosome 21. The consequences of the extra genetic material are very variable and the condition is associated with a combination of physical and mental characteristics. Although there is no specific treatment for Down’s syndrome, many of the physical health problems that are associated with the condition can be successfully managed. There are, however, currently no treatments for the memory deficits which hinder learning and delay development. People with Down’s syndrome find it difficult to use spatial and contextual information to form new memories, a process that depends on the hippocampus, but are much better at capturing sensory memories that are coordinated by the amygdala. Down’s syndrome is also associated with an increased incidence of dementia, including Alzheimer’s disease, which may be linked to an extra copy of the gene encoding the amyloid producing APP in some people with the condition.

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.

Progress in Drug Discovery for Spinal Muscular Atrophy

Image: Photobucket – Kristiarini
Image: Photobucket – Kristiarini
Spinal Muscular Atrophy (SMA) describes a group of diseases where motor neurons of the spinal cord and brain stem, which are critical for stimulation of muscle cells, degenerate and die. Lacking the appropriate input, the muscle cells become much smaller (atrophy) and patients display symptoms of muscle weakness. Affected muscles are those involved in voluntary movement and patients may have difficulty swallowing, breathing, crawling, walking and with head/neck movement. SMA is an autosomal recessive genetic disease and for a child to be affected both parents must be carriers of the abnormal gene and both must pass this gene on to their child. The incidence of SMA is estimated at 1 in 6000 births and this condition is responsible for the death of more infants than any other genetic disease.

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.

Aclarubicin
Aclarubicin
In 2001, researchers at Ohio State University showed that aclarubicin was able to restore levels of SMN in a mouse model by altering the incorporation of exon 7 into SMN2 transcripts. Although aclarubicin is too toxic to consider for development, the work prompted scientists at Paratek Pharmaceuticals to screen related tetracycline analogues. This has now resulted in the identification of PTK-SMA1, a synthetic tetracycline-like compound, as a lead candidate. PTK-SMA1, like aclarubicin, increases levels of SMN by correcting SMN2 splicing. The study, conducted in collaboration with scientists at Cold Spring Harbor and Rosalind Franklin Univeristy, is published in Science Translational Medicine.

Tetracycline
Tetracycline
Further collaborative research to progress the program to IND filing is being supported by a five-year, multi-million dollar cooperative agreement from the National Institute of Neurological Disorders and Stroke (NINDS) and by the Families of SMA funding program.

What Shall We Do with the Drunken Fruit Fly?

Drosphila Melanogaster Image: Wikipedia - André Karwath
Drosphila Melanogaster

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.

Heart Muscle Protein Rescues Mice with ‘Floppy Baby’ Syndrome

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. raggety dollMost 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.

Genes Linked to Autism

autism rights movement logoAutism, 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.