Wednesday, May 15, 2024

Is Autism A Genetic Mutation

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Forward Genetic Screen For Altered Baseline Transmission And Php

Genetic mutation linked to autism

The screen that we performed is diagrammed in Figure 2A. We took advantage of a collection of small chromosomal deficiencies that tile the 3rd chromosome, uncovering approximately 6000 genes in total. For every double heterozygous combination of RIMS1/+ with a heterozygous deficiency, we performed multiple intracellular recordings, quantifying mEPSP amplitude, EPSP amplitude, quantal content , resting membrane potential and input resistance. Recordings were made in the presence of PhTx to induce PHP. If the baseline EPSP is normal and quantal content is increased compared to wild type, then we can conclude that PHP is normally expressed. In these instances, we expect that baseline transmission was also normal in the absence of PhTx. However, if EPSPs are diminished in a given genetic combination and quantal content is not increased compared to wild type, then there are two possible origins: 1) the double mutant impairs baseline transmission or 2) baseline transmission is normal and PHP is selectively impaired. In these instances, the double heterozygous mutant combinations were re-assessed in the absence of PhTx to test for altered baseline transmission.

Screen for common genomic modifiers of ASD-associated gene mutations.
Absence of an additive effect of gene heterozygosity on synaptic transmission or PHP.

What Are Some Common Signs Of Asd

Even as infants, children with ASD may seem different, especially when compared to other children their own age. They may become overly focused on certain objects, rarely make eye contact, and fail to engage in typical babbling with their parents. In other cases, children may develop normally until the second or even third year of life, but then start to withdraw and become indifferent to social engagement.

The severity of ASD can vary greatly and is based on the degree to which social communication, insistence of sameness of activities and surroundings, and repetitive patterns of behavior affect the daily functioning of the individual.

Social impairment and communication difficultiesMany people with ASD find social interactions difficult. The mutual give-and-take nature of typical communication and interaction is often particularly challenging. Children with ASD may fail to respond to their names, avoid eye contact with other people, and only interact with others to achieve specific goals. Often children with ASD do not understand how to play or engage with other children and may prefer to be alone. People with ASD may find it difficult to understand other peoples feelings or talk about their own feelings.

Autism Genetics: A Decade Of Progress

In many ways, autism is a mysterious disorder, as it involves core abnormalities in social cognition and language, both of which are central to what makes us human. Because of this, understanding autism will have a significant impact on our basic knowledge of these fundamental cognitive processes, in addition to the obvious critical role that such mechanistic understanding has on therapeutic development. Until the last decade, virtually nothing was known about the neurobiological basis of ASD. There was no consistent neuropathology and only scant knowledge of a few causal genetic factors. The last decade has brought an explosion of genetic findings in ASD, surpassing most other common neuropsychiatric disorders, so that we now have knowledge of the etiology of ASD for between 1020% of cases. Here, I review these exciting findings with respect to what they tell us about the genetic architecture of ASD and how this informs our mechanistic understanding of the disorder and its relation to human brain function.

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Dissecting The Mechanism Of Impaired Php In A Single Double Heterozygous Mutant Combination

It is rare for a genetic study to define, precisely, how a double heterozygous interaction creates a synthetic phenotype if the two genes do not encode proteins that biochemically interact. Simply put, there are a vast number of possible mechanisms by which SSNC could occur . None-the-less, we attempted to do so for at least one double heterozygous combination. Although this represents only a single mechanism of SSNC, it could provide proof of principle for how PHP is affected in other ASD gene interactions. We chose the genetic interaction of PPP2R5D/+ with CHD8/+. This combination was chosen because CHD8 is among the most common ASD de novo gene mutations. Furthermore, the genetic interaction is highly penetrant.

We began by pursuing additional phenotypic analyses, looking for clues in a wider variety of cellular and electrophysiological measures. It is possible that the genetic interaction of PPP2R5D/+ with CHD8/+ could indirectly affect PHP expression by altering motoneuron firing properties. Therefore, we analyzed intrinsic excitability and neuronal firing by patch clamp electrophysiology of larval motoneurons. There is no change in motoneuron firing frequency in response to a series of step current pulse injection. Likewise, there are no changes in action potential amplitude, cell input resistance or rheobase comparing wild type with each single heterozygous mutation and the double heterozygote . Thus, aberrant excitability is not linked to impaired PHP.

Update Plan For Autismkb 20

Autism Genetic Mutation

To keep AutismKB 2.0 up-to-date in the future, we plan to collect ASD-related literatures from PubMed every month, which will be classified into nine categories according to their experimental methods. We will then extract the phenotype and genotype data from each study. The collected data will be manually curated every 6 months and uploaded to the back-end database through a Perl-based script. We will also recalibrate the scoring system of each evidence and gene and post an update log on the AutismKB 2.0 website .

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Single Mutation Leads To Big Effects In Autism

NIH study provides insight into one mechanism underlying the higher prevalence of males in some cases of autism.

A new study in Neuron offers clues to why autism spectrum disorder is more common in boys than in girls. National Institutes of Health scientists found that a single amino acid change in the NLGN4 gene, which has been linked to autism symptoms, may drive this difference in some cases. The study was conducted at NIHs National Institute of Neurological Disorders and Stroke .

Researchers led by Katherine Roche, Ph.D., a neuroscientist at NINDS, compared two NLGN4 genes, , which are important for establishing and maintaining synapses, the communication points between neurons.

Every cell in our body contains two sex chromosomes. Females have two X chromosomes; males have one X and one Y chromosome.; Until now, it was assumed that the NLGN4X and NLGN4Y genes, which encode proteins that are 97% identical, functioned equally well in neurons.

But using a variety of advanced technology including biochemistry, molecular biology, and imaging tools, Dr. Roche and her colleagues discovered that the proteins encoded by these genes display different functions. The NLGN4Y protein is less able to move to the cell surface in brain cells and is therefore unable to assemble and maintain synapses, making it difficult for neurons to send signals to one another. When the researchers fixed the error in cells in a dish, they restored much of its correct function.

How Do These Genes Contribute To Autism

Changes, or mutations, in the DNA of these genes, can lead to having autism spectrum disorder. Some mutations affect a single DNA base pair or letter. In fact, everyone has thousands of these genetic variants. A variant that is found in 1% or more of the population is considered common and is called a single nucleotide polymorphism .

Common variants typically have subtle effects and may work together to contribute to autism. Rare variants, which are found in less than 1% of people, tend to have stronger effects. Many of the mutations linked to autism so far have been rare. It is significantly more difficult to find common variants for autism risk, although some studies are underway.

Other changes, known as copy number variations , show up as deletions or duplications of long stretches of DNA and often include many genes. But mutations that contribute to autism are probably not all in genes, which make up less than 2% of the genome. Researchers are trying to wade into the remaining 98% of the genome to look for irregularities associated with autism. So far, these regions are poorly understood.

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How Is Asd Diagnosed

ASD symptoms can vary greatly from person to person depending on the severity of the disorder. Symptoms may even go unrecognized for young children who have mild ASD or less debilitating handicaps.

Autism spectrum disorder is diagnosed by clinicians based on symptoms, signs, and testing according to the Diagnostic and Statistical Manual of Mental Disorders-V, a guide created by the American Psychiatric Association used to diagnose mental disorders. Children should be screened for developmental delays during periodic checkups and specifically for autism at 18- and 24-month well-child visits.

Very early indicators that require evaluation by an expert include:

  • no babbling or pointing by age 1
  • no single words by age 16 months or two-word phrases by age 2
  • no response to name
  • excessive lining up of toys or objects
  • no smiling or social responsiveness

Later indicators include:

  • impaired ability to make friends with peers
  • impaired ability to initiate or sustain a conversation with others
  • absence or impairment of imaginative and social play
  • repetitive or unusual use of language
  • abnormally intense or focused interest
  • preoccupation with certain objects or subjects
  • inflexible adherence to specific routines or rituals

Evidence For Converging Molecular Pathways

Zebrafish and “Smurf Cakes” are Helping Researchers Link Autism Gene Mutation to Digestive Problems?

Several recent studies have suggested that in addition to convergent brain pathways, that there may as well be convergence at the level of molecular mechanisms in ASD. One class of such studies has asked whether putative ASD susceptibility genes are enriched in members for specific molecular or biological processes more than expected by chance. The value of this approach depends on the level of experimental support for the specific genes tested and the degree to which current pathway annotations represent reality . For genes identified within CNV this can be particularly problematic, as most known pathological CNV contain more than one gene and it is not expected that all genes within the CNV contribute to ASD, potentially increasing noise in this analysis. One recent study reduced such background by using a new phenotype-driven method to group genes within high confidence de novo CNV , identifying significant enrichment for several categories of genes, including axon outgrowth, synaptogenesis, cell-cell adhesion, GTPase signaling, and the actin cytoskeleton. These results replicate and extend earlier composite pathway analysis of putative ASD susceptibility genes compiled from the literature , and CNV pathway analysis in the Autism Genetic Resource Exchange and other cohorts . Still, these studies place ASD genes within a multiplicity of pathways, several of which are broad and do not necessarily demonstrate convergence on final common molecular processes in individuals.

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Common Phenotypic Enhancers Of Multiple Asd Gene Orthologs

How can the existence of common phenotypic modifiers be explained? We began our study with the demonstration that heterozygous LOF mutations in four unrelated ASD-associated genes including RIMS1 , CHD8 , CHD2 and ASH1L , all sensitize the expression of PHP to fail . One possibility, therefore, is that PHP is commonly sensitized to fail by heterozygous LOF mutations in each of the five ASD gene orthologs that we chose to study. If so, then a phenotypic modifier that interacts with one of these genes might also be expected to commonly interact with the other ASD genes. In other words, commonality arises because of the unexpected finding that each ASD gene ortholog has an activity that, when diminished, impairs the robustness of PHP. Our data generally support this model, given that three of four ASD genes interact with RIMS1 to block PHP. According to this model, we provide the first evidence that sensitization of PHP is a common pathophysiological effect downstream of multiple ASD genes with, as yet, unrelated biological activities.

How Gene Mutation Causes Autism And Intellectual Disability

Discovery points toward new treatment approach

Northwestern Medicine scientists have discovered why a specific genetic mutation causes intellectual disability and autism spectrum disorder in children.

We have solved an important piece of the puzzle in understanding how this mutation causes intellectual disabilities and mental illness, said lead author Peter Penzes, director of the new Center for Autism and Neurodevelopment at Northwestern University Feinberg School of Medicine.

Northwestern scientists discovered genetic mutations in human patients in a gene called Usp9x result in the brain growing fewer synapses. Thats because Usp9x protects another protein called ankyrin-G, whose role is to grow and stabilize synapses. The developing brain needs to build lots of synapses between neurons so cells can communicate while the brain grows, and to learn.

But when Usp9x is mutated, it cant stabilize the synapse-enhancing ankyrin-G. Thus, the would-be enhancer protein degrades and destabilizes, resulting in fewer synapses in the brain, scientists found. Individuals with this mutation have developmental delay, difficulty learning, increased anxiety and hyperactivity.; ;;

In addition to ankyrin-G, Usp9x also protects several other important synapse-enhancing proteins, which when mutated also cause intellectual disability and autism. Usp9x is a master-stabilizer of many key proteins essential for brain development and learning.

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A Gene Key To Early Brain Development

The research team focused on the cerebral cortex because, in humans, this part of the brain regulates higher-order functions, such as speech, consciousness, and memory.

Scientists are yet to learn exactly how the cerebral cortex develops, but they do know that a type of precursor cells which later differentiate, becoming specialized cells called radial glial cells are key to early cortical development.

These cells form at the base of the cortex in a particular design that researchers refer to as a tiled pattern. Each radial glial cell in part then generates a basal process a stem-like emanation that acts as a scaffold and helps new neurons to organize and slot into their assigned positions.

In their new animal study, the UNC researchers found that a gene called Memo1 disrupts the pattern of the radial glial cells, their basal processes, and the whole initial organization of new brain cells.

The team explains that previous studies have found that mutations in MEMO1 in humans sometimes have associations with autism. However, it remained unclear whether or how that mutation might contribute to the development of autism.

For their current research, Prof. Anton and colleagues decided to work with mice, in which they deleted the Memo1 gene in an early phase of cortical development. The team wanted to find out what effect if any, this would have on the brain.

Differential Expression Across Heterozygous Mutant Flies

Biallelic mutations in ACTL6B cause recessive autism. (A ...

Differential expression of heterozygous mutant flies was determined by pooling samples from the same genotype. Gene expression profiles between mutant and wild type were collated using the R package tximport . The R package DESeq2 used raw gene counts to determine differentially expressed genes by genotype with the linear model . Protein coding and lincRNA genes defined by the BDGP6 were included in differential expression. Expression was adjusted for batch to account for difference between fly lines, tissue source, and library preparation. The p-values were adjusted for Benjamini-Hochberg Procedure through DESeq2 with a target alpha = 0.1, and genes were considered DEGs at FDR < 0.05 and±50% expression changes.

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Do Symptoms Of Autism Change Over Time

For many children, symptoms improve with age and behavioral treatment. During adolescence, some children with ASD may become depressed or experience behavioral problems, and their treatment may need some modification as they transition to adulthood. People with ASD usually continue to need services and supports as they get older, but depending on severity of the disorder, people with ASD may be able to work successfully and live independently or within a supportive environment.

Genetic Link To Autism Found Known As Chd8 Mutation

University of Washington – Health Sciences/UW News, Community Relations & Marketing
In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. This is the first time researchers have shown a definitive cause of autism to a genetic mutation. Previously identified genetic events like Fragile X, which account for a greater number of autism cases, are associated with other impairments, such as intellectual disability, more than autism.

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: “Disruptive CHD8 Mutations Define a Subtype of Autism in Early Development.”

“We finally got a clear cut case of an autism specific gene,” said Raphael Bernier, the lead author, and UW associate professor in the Department of Psychiatry and Behavioral Sciences and the clinical director of the Autism Center at Seattle Children’s.

Bernier said people with a mutation in the CHD8 gene have a very “strong likelihood” that they will have autism marked by gastrointestinal disorders, a larger head and wide set eyes.

In their study of 6,176 children with autism spectrum disorder, researchers found 15 had a CHD8 mutation and all these cases had similar characteristics in appearance and issues with sleep disturbance and gastrointestinal problems.

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What Research Is Being Done

The mission of the National Institute of Neurological Disorders and Stroke is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health , the leading supporter of biomedical research in the world.; NINDS and several other NIH Institutes and Centers support research on autism spectrum disorder.;

Nearly 20 years ago the NIH formed the Autism Coordinating Committee to enhance the quality, pace, and coordination of efforts at the NIH to find a cure for autism. The NIH/ACC has been instrumental in promoting research to understand and advance ASD. The NIH/ACC also participates in the broader;Federal Interagency Autism Coordinating Committee , composed of representatives from various U.S. Department of Health and Human Services agencies, the Department of Education, and other governmental organizations, as well as public members, including individuals with ASD and representatives of patient advocacy organizations. One responsibility of the IACC is to develop a strategic plan for ASD research, which guides research programs supported by NIH and other participating organizations.

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