Linkage and candidate gene studies of autism spectrum disorders in European populations

Holt, R. J.; Barnby, Gabrielle; Maestrini, Elena; Bacchelli, Elena; Brocklebank, Denise; Sousa, Inês; Mulder, E.; Kantojärvi, Katri; Järvelä, Irma; Klauck, Sabine M.; Poustka, Fritz; Bailey, Anthony; Monaco, Anthony P.

doi:10.1038/ejhg.2010.69

Cited by 84 publications

(74 citation statements)

References 49 publications

(43 reference statements)

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“…Characterization of the M867I missense mutation revealed no detectable effect on GluK2 receptor gating (Han et al, 2010), but revealed a modest ∼1.6-fold slowing of the desensitization time course. Additional SNP association studies on various populations support a role of GRIK2 in autism (Shuang et al, 2004;Dutta et al, 2007;Kim et al, 2007;Holt et al, 2010;Casey et al, 2012;Griswold et al, 2012). …”

Section: Kainate-selective Glutamate Receptorsmentioning

confidence: 94%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

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The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

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Section: Kainate-selective Glutamate Receptorsmentioning

confidence: 94%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

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“…88 Association analysis showed strong coupling of MKL2 (MKL/myocardin-like 2) and TSN with autism in at least two European populations, Finnish and Northern Dutch ones. This raises the question: does TSN have a direct role in the development of this or any other diseases and if so, what are potential mechanisms of its function?…”

Section: Discussionmentioning

confidence: 99%

Tudor staphylococcal nuclease: biochemistry and functions

et al. 2016

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Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) is an evolutionarily conserved protein with invariant domain composition, represented by tandem repeat of staphylococcal nuclease domains and a tudor domain. Conservation along significant evolutionary distance, from protozoa to plants and animals, suggests important physiological functions for TSN. It is known that TSN is critically involved in virtually all pathways of gene expression, ranging from transcription to RNA silencing. Owing to its high protein-protein binding affinity coexistent with enzymatic activity, TSN can exert its biochemical function by acting as both a scaffolding molecule of large multiprotein complexes and/or as a nuclease. TSN is indispensible for normal development and stress resistance, whereas its increased expression is closely associated with various types of cancer. Thus, TSN is an attractive target for anti-cancer therapy and a potent tumor marker. Considering ever increasing interest to further understand a multitude of TSN-mediated processes and a mechanistic role of TSN in these processes, here we took an attempt to summarize and update the available information about this intriguing multifunctional protein. TSN is an evolutionarily conserved protein having a pivotal role in the regulation of gene expression. TSN acts both as a scaffolding protein and as a nuclease. TSN sustains cell viability and its cleavage by proteases facilitates cell death. TSN is implicated in key cancer-related processes and is a potent marker of various types of tumors. Open questions:How is nucleolytic activity of TSN regulated in vivo and how this affects interaction of TSN with downstream targets? What are the structural bases and functional consequences of distinct intracellular localization patterns of TSN in animals and plants? What are the molecular mechanisms of the TSN-mediated cancerogenesis?God has given you one face, and you make yourself another (William Shakespeare). Being true for all living organisms, accurate spatio-temporal regulation of gene expression is a fundamental mechanism underlying development, homeostasis and adaptation to the environment. Eukaryotic gene expression is a cumulative outcome of a multitude of molecular processes, including transcription, mRNA splicing, stability and translation, chromatin modification, as well as protein stability and modification. Each of these processes is in turn controlled by a highly dedicated repertoire of proteins. However, one protein, Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) appears to act in most of the gene expression pathways.TSN is an evolutionarily conserved protein found in all eukaryotic lineages, except budding yeast, Saccharomyces cerevisiae. Conservation along significant evolutionary distance suggests important physiological functions for TSN. Invariant domain composition of TSN comprises tandem repeat of four staphylococcal nuclease (SN)-like domains (hereafter referred to as SN domains) at the N terminus and a fusio...

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“…The RELN gene encodes a large extracellular matrix protein that organizes neuronal positioning during corticogenesis and is regulated by epigenetic mechanisms. Several independent studies have shown an association between RELN and ASD (Skaar et al, 2005;Ashley-Koch et al, 2007;Holt et al, 2010). Interestingly, reduced levels of reelin and its isoforms have been previously shown in autistic twins and their first degree relatives (Fatemi et al, 2005).…”

Section: Epigenetic Contributionsmentioning

confidence: 90%

Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities

Kaufman¹,

Noor²,

Ayub³

et al. 2011

Autism Spectrum Disorders: The Role of Genetics in Diagnosis and Treatment

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Linkage and candidate gene studies of autism spectrum disorders in European populations

Cited by 84 publications

References 49 publications

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Tudor staphylococcal nuclease: biochemistry and functions

Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities

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