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Thread: Researchers Pinpoint Gene Responsible for Autism

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    Researchers Pinpoint Gene Responsible for Autism

    A study led by researchers at McMaster University has pinpointed a gene that is responsible for neurodevelopmental disorders, including autism.

    Researchers found alterations of the gene thousand and one amino-acid kinase 2, known as TAOK2, plays a direct role in these disorders. This is the first comprehensive study that supports previous research suggesting the involvement of this gene.

    The study was published in Molecular Psychiatry.

    "Our studies reveal that in complex brain disorders that have a loss of many genes, a single deleted gene is sufficient to cause symptoms for the patients," said Karun Singh, study co-author and researcher with McMaster's Stem Cell and Cancer Research Institute.

    "This is exciting because it focuses our research effort on the individual gene, saving us time and money as it will speed up the development of targeted therapeutics to this gene alone."

    Many neurodevelopmental disorders are caused by large missing pieces of genetic material in a person's genome that contain several genes, termed a 'microdeletion'. Accurately diagnosing a gene microdeletion helps doctors to predict patient outcome and to determine if a new treatment is available.

    The researchers used genetically engineered models and computer algorithms to study a human genome, which allowed them to pinpoint the single gene in question.

    "Our next step is to screen candidate drugs that correct the cognitive brain deficits caused by genetic mutations in TAOK2, and identify candidates for pilot clinical trials," said Singh, who also holds the David Braley Chair in Human Stem Cell Research and is an assistant professor in biochemistry and biomedical sciences at McMaster.

    The paper complements a study led by Singh on gene microdeletion published in American Journal of Human Genetics in early February.

    "The investment into the Braley Chair for Dr. Singh and his development of key collaborations is building in multiple directions beyond what we initially imagined," said Mick Bhatia, director of McMaster's Stem Cell and Cancer Research Institute. "The combination of patient specific genetics and stem cell technologies is likely to be transformative in the near term for brain disorders."

    https://medicalxpress.com/news/2018-...rs-autism.html

    http://www.cell.com/ajhg/fulltext/S0002-9297(18)30006-5
    https://www.nature.com/articles/s41380-018-0025-5

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    Interesting my brother has Autism so really it's thanks to loss of a gene and a mess up from TAOK2. Hmm now it's more simpler now

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    Quote Originally Posted by AdeoF View Post
    Interesting my brother has Autism so really it's thanks to loss of a gene and a mess up from TAOK2. Hmm now it's more simpler now
    According to the CDC, it affects 1 in 68 children. I wonder what is causing this affect to this particular gene. But now that they've pinpointed the issue, perhaps they can get to the bottom of it. Moreover, with things like gene editing, they'll be able to prevent it in the future.

    https://www.cdc.gov/ncbddd/autism/data.html

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    1 members found this post helpful.
    Quote Originally Posted by Jovialis View Post
    A study led by researchers at McMaster University has pinpointed a gene that is responsible for neurodevelopmental disorders, including autism.

    Researchers found alterations of the gene thousand and one amino-acid kinase 2, known as TAOK2, plays a direct role in these disorders. This is the first comprehensive study that supports previous research suggesting the involvement of this gene.

    The study was published in Molecular Psychiatry.

    "Our studies reveal that in complex brain disorders that have a loss of many genes, a single deleted gene is sufficient to cause symptoms for the patients," said Karun Singh, study co-author and researcher with McMaster's Stem Cell and Cancer Research Institute.

    "This is exciting because it focuses our research effort on the individual gene, saving us time and money as it will speed up the development of targeted therapeutics to this gene alone."

    Many neurodevelopmental disorders are caused by large missing pieces of genetic material in a person's genome that contain several genes, termed a 'microdeletion'. Accurately diagnosing a gene microdeletion helps doctors to predict patient outcome and to determine if a new treatment is available.

    The researchers used genetically engineered models and computer algorithms to study a human genome, which allowed them to pinpoint the single gene in question.

    "Our next step is to screen candidate drugs that correct the cognitive brain deficits caused by genetic mutations in TAOK2, and identify candidates for pilot clinical trials," said Singh, who also holds the David Braley Chair in Human Stem Cell Research and is an assistant professor in biochemistry and biomedical sciences at McMaster.

    The paper complements a study led by Singh on gene microdeletion published in American Journal of Human Genetics in early February.

    "The investment into the Braley Chair for Dr. Singh and his development of key collaborations is building in multiple directions beyond what we initially imagined," said Mick Bhatia, director of McMaster's Stem Cell and Cancer Research Institute. "The combination of patient specific genetics and stem cell technologies is likely to be transformative in the near term for brain disorders."

    https://medicalxpress.com/news/2018-...rs-autism.html

    http://www.cell.com/ajhg/fulltext/S0002-9297(18)30006-5
    https://www.nature.com/articles/s41380-018-0025-5
    Wouldn't it be wonderful if they could just fix the gene?


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    Quote Originally Posted by Angela View Post
    Wouldn't it be wonderful if they could just fix the gene?
    Indeed, it would be wonderful, and it would make the lives of others much easier.

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    Quote Originally Posted by Jovialis View Post
    Indeed, it would be wonderful, and it would make the lives of others much easier.
    They really need to target things like schizophrenia and even bi-polar disorder too, although I think those will be much harder fixes because we already know that a lot of genes are involved.

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    As crazy as this may sound, I would be hesitant to "cure" my disorders bc they partially define who I am. I'll also add that treatment brings me the best of both worlds.
    mmmmmmmmm dooouuughhhnuuuutz

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    Get the cure. You’ll worry about the rest later.

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    To be honest autism can't be cured right now but if it's mild enough the person with it can control it. Gene editing is great to "cure" it but I am worried if it goes wrong. This study has made it easier to understand it and hopefully more testing will be done in the future on it, so one day people can understand it better

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    Working towards solutions one step at a time

    Thanks you for your great idea> The cdc.gov is a wealth of information. Andrew Solomon's "Far From the Tree" His section on Autism talks from many perspectives about what it takes for family and friends.
    "Autism Parents are Activist." One of a family's biggest roles on the stage of the assignments of a daily following. The need to identify the genetics seems to prove that their's always more than one step.
    Neurodevelopmental disorders include various conditions characterized by deficits or delays in typical developmental milestones that appear in childhood. Genetic studies indicate that copy-number variations (CNVs), comprising deletions or duplications of genomic DNA that may directly or indirectly affect the dosage of genes, can be significant risk factors for these disorders. Certain genomic contexts are hotspots for recombination- and replication-based mechanisms that result in microdeletions or microduplications. While 5%–20% of developmentally delayed individuals carry a rare large pathogenic CNV,1 the pathobiology is poorly understood. Furthermore, for most CNVs associated with neurodevelopmental disorders, the underlying genes that contribute to the clinical phenotypes remain unknown. The 22q11.2 and 16p11.2 microdeletions are two specific CNVs associated with schizophrenia (MIM: 181500) and autism spectrum disorder (ASD) (MIM: 209850), respectively, in which substantial progress has been made into the understanding of disease pathophysiology.2, 3, 4, 5, 6, 7, 8, 9 In both, modeling microdeletions in animal models has accelerated the pace at which the underlying biological pathogenic mechanism(s) have been identified and has provided a means to test potential “driver genes” underlying CNV-associated phenotypes.10, 11, 12, 13, 14 Importantly, these studies have led to potential drug therapies that have been tested in preclinical mouse models,5, 7, 15 highlighting the power of this approach.

    The 15q13.3 1.53 Mb microdeletion syndrome (MIM: 612001) locus (chr15:30,910,306–32,445,407 [hg19]) that resides within breakpoints BP4-BP5 on human chromosome 15 is a recurrent CNV that results in a highly heterogeneous set of phenotypes including intellectual disability (50%–60%), autism spectrum disorder (10%–20%), epilepsy (30%) (MIM: 607208), and schizophrenia (10%–20%).16, 17, 18, 19, 20, 21, 22, 23 Among the more than 200 individuals bearing 15q13.3 BP4-BP5 deletions who have been described in the clinical literature, 80% exhibited ascertainment-independent phenotypic manifestations; this implies that one or more genes in the CNV may contribute to disease manifestation, including the incomplete penetrance and variable expressivity observed.24 Individuals are typically heterozygous for the 15q13.3 microdeletion, which encompasses seven protein-coding genes, one microRNA, and two putative pseudogenes (ARHGAP11BI [MIM: 616310], LOC100288637, FAN1 [MIM: 613534], MTMR10, TRPM1 [MIM: 603576], LOC283710, microRNA-211, KLF13 [MIM: 605328], OTUD7A [MIM: 612024], and CHRNA7 [MIM: 118511]). Recently, a heterozygous mouse model of the 15q13.3 microdeletion was generated (Df(h15q13)/+ mice) that contains a deletion of the syntenic murine chromosome region (mouse chromosome 7qC) corresponding to the human CNV. Phenotypic manifestations of this heterozygous mouse model include schizophrenia- and epilepsy-related endophenotypes, notably long-term spatial memory deficits, increased sensitivity to stress, and reductions in auditory-evoked gamma power (similar to schizophrenia patients).25 Many of these observed clinical phenotypes were replicated in another independent 15q13.3 heterozygous microdeletion mouse model.26
    In contrast to the heterozygous deletion, the homozygous deletion is extremely rare and only eight case subjects have been reported in the literature.24, 27, 28 All reported case subjects that carry the homozygous deletion manifested severe cognitive and physiological impairments including severe DD/ID, hypotonia, seizures, and visual impairment.24 A recent study analyzed behavioral abnormalities of Df(h15q13)/ homozygous knock out (KO) mice29 in which both copies of the genes within the locus are deleted.27 While the majority of human case subjects are carriers of a heterozygous microdeletion, the homozygous KO mice displayed more pronounced phenotypes in seizure susceptibility, ASD behavior-related phenotypes, and auditory sensory processing, demonstrating a gene-dosage dependency. While the underlying neurophysiological abnormalities remain unknown, recent studies using resting-state fMRI have revealed that Df(h15q13)/+ mice display altered neuronal firing rates in the prefrontal cortex30 and abnormal brain hyperconnectivity patterns;31 however, the underlying molecular and physiological brain abnormalities contributing to the mouse behavioral, imaging, and electrophysiological phenotypes remain unknown.
    The complexities inherent in the identification of the critical driver gene(s) in a given CNV are significant and require evidence from multiple sources. With regard to the 15q13.3 microdeletion, CHRNA7 (encoding a cholinergic receptor) has been proposed as a driver gene, in part because some patients have overlapping deletions that encompass CHRNA7.20 Furthermore, CHRNA7 agonists may improve cognition in humans with schizophrenia32 and abnormal fMRI-derived brain connectivity in Df(h15q13)/+ mice.31 However, Chrna7 KO mice display very mild defects in synaptic function and learning33, 34, 35, 36 and have no consistent behavioral or neurophysiological phenotypes compared to Df(h15q13)/+ mice.37 Furthermore, among clinical case subjects, many of the deletions encompassing CHRNA7 also overlap the adjacent gene OTUD7A.20 One study reported 43 case subjects from the literature that had deletions encompassing both CHRNA7 and the first exon of OTUD7A.24 The Database of Genomic Variants (DGV) includes population control subjects that carry CHRNA7 deletions, bringing into question the penetrance of haplo-insufficiency of CHRNA7.38, 39 Another possible candidate is FAN1, which encodes a DNA repair enzyme. Rare nonsynonymous variants have been found in this gene among individuals with ASD or schizophrenia.40 Consequently, other genes in the 15q13.3 microdeletion could contribute to disease pathogenesis.
    Here, we used multiple in silico, in vivo, and in vitro strategies to dissect the cellular phenotypes and critical loci that contribute to the 15q13.3 microdeletion syndrome. By using the Df(h15q13)/+ heterozygous mouse model, RNA sequencing, signaling pathway analysis, and neuronal morphology analysis, we discovered that developing cortical excitatory neurons have deficiencies in dendrite and synapse growth (Figure S2). We concurrently identified candidate gene(s) within this syndromic region contributing to these phenotypes by applying developmental human brain expression (transcriptome and proteome) data analysis together with whole-genome and -exome sequencing data from individuals with neurodevelopmental disorders and ASD.41 These analyses identified a strong candidate gene, OTUD7A, within the 15q13.3 microdeletion syndrome region, which encodes a putative deubiquitinating enzyme that localizes to dendritic spine compartments and has a protein-protein co-expression network that includes synaptic and dendritic signaling pathways. We biologically validated OTUD7A and found that re-expressing OTUD7A WT into cortical neurons from Df(h15q13)/+ mice rescued the dendritic spine defects. However, a mutant OTUD7A harboring an ASD-linked de novo exonic mutation was unable to rescue these defects. Furthermore, we found that both OTUD7A and CHRNA7 contribute to the dendrite outgrowth defects. Our data identify OTUD7A as a candidate gene that contributes to abnormalities in cortical neuron dendritic and spine development and a critical gene in the phenotypic manifestation of the 15q13.3 microdeletion syndrome.
    It's hard to weigh one priority with another yet this disease affects everyone and demands our attention. Thanks again for including it in today's threads.

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    3 members found this post helpful.
    Quote Originally Posted by AdeoF View Post
    Interesting my brother has Autism so really it's thanks to loss of a gene and a mess up from TAOK2. Hmm now it's more simpler now
    No, it's not that simple. This study identified one more gene linked to autism, but there are over 50 genes associated with ASD (not in every one, as autism isn't one condition, but a patchwork of conditions, hence the jigsaw puzzle as the logo for ASD). Gene therapy (fixing the genes) will surely become one possible therapy in the coming years. However not all cases of autism are genetic. Some are caused by toxins, trauma or even immune dysfunctions.
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