Posts Tagged ‘Mutation’


[link to research article on loss-of-function variants in the human genome]

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Where's Waldo in Google Maps?
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In an earlier post on Williams Syndrome, we delved into the notion that sometimes a genetic variant can lead to enhanced function – such as certain social behaviors in the case of WS.  A mechanism that is thought to underlie this phenomenon has to do with the way in which information processing in the brain is widely distributed and that sometimes a gene variant can impact one processing pathway, while leaving another pathway intact, or even upregulated.  In the case of Williams Syndrome a relatively intact ventral stream (“what”) processing but disrupted dorsal stream (“where”) processing leads to weaker projections to the frontal cortex and amygdala which may facilitate gregarious and prosocial (a lack of fear and inhibition) behavior.  Other developmental disabilities may differentially disrupt these 2 visual information processing pathways.  For instance, developmental dyspraxia contrasts with WS as it differentially disrupts the ventral stream processing pathway.

A recent paper by Woodcock and colleagues in their article, “Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader–Willi syndrome” [doi:10.1016/j.neuropsychologia.2008.09.019] ask how another developmental disability – Prader-Willi syndrome – might differentially influence the development of these information processing pathways.  PWS arises from the lack of expression (via deletion or uniparental disomy) of a cluster of paternally expressed genes in the 15q11-13 region (normally the gene on the maternally inherited chromosome is silent, or imprintedrelated post here).  By comparing PWS children to matched controls, the team reports evidence showing that PWS children who carry the deletion are slightly more impaired in a task that depends on the dorsal “where” pathway whilst some sparing or relative strength in the ventral “what” pathway.

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Summer, Brody and Audric Hug
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If you have a minute, check out this “Autism Sensory Overload Simulation” video to get a feel for the perceptual difficulties experienced by people with autism spectrum disorders.  A recent article, “Critical Period Plasticity Is Disrupted in the Barrel Cortex of Fmr1 Knockout Mice” [doi: 10.1016/j.neuron.2010.01.024] provides some clues to the cellular mechanisms that are involved in this phenomenon.  The authors examined the developing somatosensory cortex in lab mice who carry a mutation in a gene called FMR1.  The normal function of this gene is to help synapses mature and optimize their strength through a process known as activity-dependent plasticity.  This a kind of “use-it-or-lose-it” neural activity that is important when you are practicing and practicing to learn something new – say, like riding a bike, or learning a new language.  Improvements in performance that come from “using” the circuits in the brain are correlated with optimized synaptic connections – via a complex set of biochemical reactions (eg. AMPA receptor trafficking).

When FMR1 is not functioning, neuronal connections (in this case, synapses that connect the thalamus to the somatosensory cortex) cannot mature and develop properly.  This wreaks havoc in the developing brain where maturation can occur in successive critical periods – where the maturation of one circuit is needed to ensure the subsequent development of another.  Hence, the authors suggest, the type of sensory overload reported in the autism spectrum disorders may be related to a similar type of developmental anomaly in the somatosensory cortex.

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Just a pointer to onetime University of Edinburgh Professor C.H. Waddington’s 1972 Gifford Lecture on framing the genes vs. environment debate of human behavior.  Although Waddington is famous for his work on population genetics and evolutionary change over time, several of his concepts are experiencing some resurgence in the neuroimaging and psychological development literatures these days.

One term, CHREOD, combines the Greek word for “determined” or “necessary” and the word for “pathway.” It describes a system that returns to a steady trajectory in contrast to homeostasis which describes a system which returns to a steady state.  Recent reviews on the development of brain structure have suggested that the “trajectory” (the actual term “chreod” hasn’t survived) as opposed to any specific time point is the essential phenotype to use for understanding how genes relate to psychological development.  Another term, CANALIZATION, refers to the ability of a population to produce the same phenotype regardless of variability in its environment or genotype.  A recent neonatal twin study found that the heritability of grey matter in neonatal humans was rather low.  However it seems to then rise until young adulthood – as genetic programs presumably kick-in – and then decline again.  Articles by neurobiologist Jay N. Giedd and colleagues have suggested that this may reflect Waddington’s idea of canalization.  The relative influence of genes vs. environment may change over time in ways that perhaps buffer against mutations and/or environmental insults to ensure the stability and robustness of functions and processes that are both appropriate for survival and necessary for future development.  Another Waddington term, EPIGENETIC LANDSCAPE, refers to the limitations on how much influence genes and environment can have on the development of a given cell or structure.  Certainly the environment can alter the differentiation, migration, connectivity, etc. of neurons by only so much.  Likewise, most genetic mutations have effects that are constrained or compensated for by the larger system as well.

Its amazing to me how well these evolutionary genetic concepts capture the issues at the nexus of of genetics and cognitive development.  From his lecture, it is clear that Waddington was not unaware of this.  Amazing to see a conceptual roadmap laid out so long ago.  Digging the book cover art as well!

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The cognitive and emotional impairments in the autism spectrum disorders can be difficult for parents and siblings to understand and cope with.  Here are some graphics and videos that might assist in understanding how genetic mutations and epigenetic modifications can lead to various forms of social withdrawl commonly observed in the autism spectrum disorders in children.

In this post, the focus is just on the MecP2 gene – where mutations are known to give rise to Rett Syndrome – one of the autism spectrum disorders.  I’ll try and lay out some of the key steps in the typical bare-bones-link-infested-blogger-fashion – starting with mutations in the MecP2 gene.  Disclaimer: there are several fuzzy areas and leaps of faith in the points and mouse model evidence below, and there are many other genes associated with various aspects of autism spectrum disorders that may or may not work in this fashion.  Nevertheless, still it seems one can begin to pull a mechanistic thread from gene to social behavior Stay tuned for more on this topic.

1. The MecP2 gene encodes a protein that binds to 5-Methylcytosine – very simply – a regular cytosine reside with an extra methyl group added at position 5.  Look at the extra -CH3 group on the cytosine residue in the picture at right.  See?  That’s a 5-methylcyctosine residue – and it pairs in the DNA double helix with guanosine (G) in the same fashion as does the regular cyctosine reside (C). 5methC OK, now, mutations in the gene that encode the  MecP2 gene – such as those found at Arginine residue 133 and Serine residue 134 impair the ability of the protein to bind to these 5-Methylcyctosine residues.  bindingMecP2The figure at left illustrates this, and shows how the MecP2 protein lines up with the bulky yellow 5-Methylcytosine residues in the blue DNA double helix during binding.

2. When the MecP2 protein is bound to the methylated DNA, it serves as a binding site for another type of protein – an HDAC or histone deacetylase. The binding of MecP2 and HDAC (and other proteins (see p172 section 5.3 of this online bookChromatin Structure and Gene Expression“)).  The binding of the eponymously named HDAC’s leads to the “de-acetylation” of proteins known as histones.  The movie below illustrates how histone “de-acetylation” leads to the condensation of DNA structure and repression or shutting down of gene expression (when the DNA is tightly coiled, it is inaccessible to transcription factors).  Hence: DNA methylation leads (via MecP2, HDAC binding) to a repression on gene expression.

3. When mutated forms of MecP2 cannot bind, the net result is MORE acetylation and MORE gene expression. As covered previously here, this may not be a good thing during brain development since more gene expression can induce the formation of more synapses and – possibly – lead to neural networks that fail to grow and mature in the “normal” fashion. The figure at right toomanysynapsessuggests that neural networks with too many synapses may not be appropriately connected and may be locked-in to sub-optimal architectures.  Evidence for excessive synaptogenesis is abundant within the autism spectrum disorders.  Neuroligins – a class of genes that have been implicated in autism are known to function in cell & synaptic adhesion (open access review here), and can alter the balance of excitation/inhibition when mutated – which seems consistent with this heuristic model of neural networks that can be too adhesive or sticky.

4. Cognitive and social impairment can result from poor-functioning neural networks containing, but not limited to the amygdala. The normal development of neural networks containing the forntal cortex and amygdala are important for proper social and emotional function.  The last piece of the puzzle then would be to find evidence for developmental abnormalities in these networks and to show that such abnormalities mediate social and/or emotional function.  Such evidence is abundant.

Regarding the effects of MecP2 however, we can consider the work of Adachi et al., who were able to delete the MecP2 gene – just in the amygdala – of (albeit, an adult) mouse.  Doing so, led to the disruption of various emotional behaviors – BUT NOT – of various social interaction deficits that are observed when MecP2 is deleted in the entire forebrain.  This was the case also when the team infused HDAC inhibitors into the amygdala suggesting that loss of transcriptional repression in the adult amygdala may underlie the emotional impariments seen in some autism spectrum disorders.  Hence, such emotional impairments (anxiety etc.) might be treatable in adults (more on this result later and its implications for gene-therapy).

Whew!  Admittedly, the more you know – the more you don’t know.  True here, but still amazing to see the literature starting to interlink across human-genetic, mouse-genetic, human-functional-imaging levels of analysis. Hoping this rambling was helpful.

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English: Visualization of a DTI measurement of...
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Within the genetic news flow, there is often, and rightly so, much celebration when a gene for a disease is identified.  This is indeed an important first step, but often, the slogging from that point to a treatment – and the many small breakthroughs along the way – can go unnoticed. One reason why these 2nd (3rd, 4th, 5th …) steps are so difficult, is that in some cases, folks who carry “the gene” variant for a particular disorder, do not, in fact, display symptoms of the disorder.

Huh? One can carry the risk variant – or many risk variants – and not show any signs of illness?  Yes, this is an example of what geneticists refer to as variable penetrance, or the notion of carrying a mutation, but not outwardly displaying the mutant phenotype.  This, is one of the main reasons why genes are not deterministic, but much more probablistic in their influence of human development.

Of course, in the brain, such complexities exist, perhaps even moreso.  For example, take the neurological condition known as dystonia, a movement disorder that, according to the Dystonia Medical Research Foundation, “causes the muscles to contract and spasm involuntarily. The neurological mechanism that makes muscles relax when they are not in use does not function properly. Opposing muscles often contract simultaneously as if they are “competing” for control of a body part. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures.”  Presently there are more than a dozen genes and/or chromosomal loci that are associated with dystonia – two of the major genes, DYT1 and DYT6 – having been identified as factors in early onset forms of dystonia.  Now as we enter the era of personal genomes, an individual can assess their (own, child’s, preimplantion embryo’s!) genetic risk for such rare genetic variants – whose effects may not be visible until age 12 or older.  In the case of DYT1, this rare mutation (a GAG deletion at position 946 which causes a loss of a glutamate residue in the torsin A protein) gives rise to dystonia in about 30-40% of carriers.  So, how might these genes work and why do some individuals develop dystonia and others do not?  Indeed, these are the complexities that await in the great expanse between gene identification and treatment.

An inspection of the molecular aspects of torsin A (DYT1) show that it is a member of the AAA family of adenosine triphosphatases and is related to the Clp protease/heat shock family of genes that help to properly fold poly-peptide chains as they are secreted from the endoplasmic reticulum of the cell – a sort-of handyman, general purpose gene (expressed in almost every tissue in the body) that sits on an assembly line and hammers away to help make sure that proteins have the right shape as they come off their assembly linesNot much of a clue for dystonia – hmm.  Similarly, the THAP domain containing, apoptosis associated protein 1 (THAP1) gene (a.k.a. DYT6) is also expressed widely in the body and seems to function as a DNA binding protein that regulates aspects of cell cycle progression and apoptosis.  Also not much an obvious clue to dystonia – hmm, hmm.  Perhaps you can now see why the identification of “the gene” – something worth celebrating – can just leave you aghast at how much more you don’t know.

That these genes influence an early developmental form of the disorder suggests a possible developmental role for these rather generic cogs in the cellular machinery.  But where? how? & why an effect in some folks and not others?  To these questions, comes an amazing analysis of DYT1 and DYT6 carriers in the article entitled, “Cerebellothalamocortical Connectivity Regulates Penetrance in Dystonia” by Argyelan and colleagues [doi: 10.1523/JNEUROSCI.2300-09.2009]. In this article, the research team uses a method called diffusion tensor imaging (sensitive to white matter density) to examine brain structure and function among individuals who carry the mutations but either DO or DO NOT manifest the symptoms. By looking at white matter tracts (super highways of neural traffic) throughout the brain the team was able to ask whether some tracts were different in the 2 groups (as well as a group of unaffectd, non-carriers).  In this way, the team can begin to better understand the causal pathway between these run-of-the-mill genes (torsin A and thap1) and the complex pattern of muscle spasms that arise from their mutations.

To get right to the findings, the team has discovered that in one particular tract, a superhighway known as “cerebellar outflow pathway in the white matter of lobule VI, adjacent to the dentate nucleus” (not as quaint as Route 66) that those participants that DO manifest dystonia had less tract integrity and connectivity there compared to those that DO NOT manifest and healthy controls (who have the most connectivity there).  Subsequent measures of resting-state blood flow confirmed that the disruptions in white matter tracts were correlated with cerebellar outflow to the thalamus and – more importantly – with activity in areas of the motor cortex.  The correlations were such that individuals who DO manifest dystonia had greater activity in the motor cortex (this is what dystonia really comes down to — too much activity in the motor cortex).

Thus the team were able to query gene carriers using their imaging methods and zero-in on “where in the brain” these generic proteins exert a detrimental effect.  This seems to me, to be a huge step forward in understanding how a run-of-the-mill gene can alter brain function in such a profound way.  Now that they’ve found the likely circuit (is it the white matter per se or the neurons?), more focus can be applied to how this circuit develops – and can be repaired.

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If you like gardening, the doldrums of winter can be dreary indeed. Although I’d never admit to it, my neighbors might swear to having seen me outside strangely (pathetically) counting the number of branches on my icicle-laden roses and rhododendrons.  In any case, I do admit to spending way too much time forlornly staring at my garden from the window while fantasizing about all the things I’ll plant come springtime.

Each new branch brings a new burst of color and fragrance and concomitant joy.  A good thing right ?  Similarly, each neuron in the brain – which look just like little trees with branches – should also strive to send out as many new branches and make new synaptic connections.  Afterall, there are brain disorders associated with a loss of or fewer dendrites, such as Down’s syndrome and schizophrenia. More branches, more synapses, more brain power and concomitant joy ? Well, perhaps not quite.

A gene known as seizure-related gene 6 (sez6) which is expressed in the developing brain as well as in response to environmental stimulation, seems to play a role in limiting the the number of branches that a neuron can send out.  Gunnersen and colleagues [doi: 10.1016/j.neuron.2007.09.018] show that mice that carry an inactivated version of sez6 show more dendritic branches (implying that the normal function of the active gene is to inhibit branch formation), and that this is definitely not a good thing.  These sez6(-/-) mice, while looking rather indistinguishable from their normal littermates, did not perform as well on tasks involving motor control, memory and emotional sensitivity (implying that having too many branches may not be so beneficial).  In humans, a frameshift mutation involving an insertion of a C residue at position 1435 of the cDNA is associated with febrile seizures, similarly suggesting that dendritic overload can have negative effects on human brain function.

Clearly, the human brain seeks a balance between too many and too few dendritic branches.  I suppose most experienced gardeners would also agree that too many branches is not desirable.  Perhaps they are right.  However, I don’t think I’d mind much if plants came with an analogous sez6 mutation !

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