Zebrafish gene knockdowns imply roles for human <i>YWHAG</i> in infantile spasms and cardiomegaly

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

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“…44 Interestingly, zebrafish knocked down for YWHAG have reduced brain size and an increased diameter of the heart tube. 45 …”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of severity in multiple sclerosis

Briggs¹,

Shao²,

Goldstein³

et al. 2011

Genes Immun

105

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“…Moreover, based on ywhag1 knockdown phenotype and expression pattern, the hemizigosity of YWHAG has been proposed to contribute to epilepsy and cardiomegaly. 14 In a recent study, Ramocki et al 10 reported individuals with heterozygous microdeletions distally adjacent to the WBS region inclusive of HIP1, but not YWHAG in patients with variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities, suggesting that deletion of HIP1 is sufficient to cause neurological disease. Together with these collective findings, our results led to the postulation that HIP1 and YWHAG genes might contribute to the WBS neurological dysfunction when deleted along with other WBS genes.…”

Section: Patient Wbs166mentioning

confidence: 99%

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

et al. 2013

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syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry B3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of B1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.

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“…The biological mechanism(s) of ISS in these syndromes are not known, except for Miller-Dieker syndrome in which the deletion of PAFAH1B1/LIS1 causes both abnormal primary glutamatergic and GABAergic interneuron migration [89, 96, 97]. Similarly, deletion of MAGI2 at 7q11.2 may be associated with ISS in Williams syndrome [16], although there are also reports of ISS in Williams syndrome patients with deletions that do not include MAGI2 [25, 98, 99]. Overall this suggests that copy number changes in key genes, in the right developmental context, influence the occurrence of ISS in these disorders.…”

Section: Iss With Predisposing Genotype Knownmentioning

confidence: 99%

Genetic and Biologic Classification of Infantile Spasms

Paciorkowski

Thio

Dobyns

2011

Pediatric Neurology

146

125

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Infantile spasms are an age-dependent epilepsy that are highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems have focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with the recent discoveries of mutations in genes in key pathways of central nervous system development in patients with infantile spasms. Children with certain genetic syndromes are much more likely to have infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children with these genetic associations with infantile spasms also have phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. We therefore also propose a biologic classification of the genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on that data. The two best described pathways of pathogenesis are abnormalities in the gene regulatory network of GABAergic forebrain development, and abnormalities in molecules expressed at the synapse. We intend for these genetic and biologic classifications to be flexible, and hope that they will encourage much needed progress in syndrome recognition, clinical genetic testing, and ultimately the development of new therapies that target specific pathways of pathogenesis.

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Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly

Cited by 36 publications

References 29 publications

Genome-wide association study of severity in multiple sclerosis

Genome-wide association study of severity in multiple sclerosis

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

Genetic and Biologic Classification of Infantile Spasms

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