A woman with 46,XX,dup(16)(p13.11 p13.3) and the ATR-X phenotype

Akahoshi, Keiko; Ohashi, Hironori; Hattori, Yukio; Saitoh, Shinji; Fukushima, Yoshimitsu; Wada, Takahito

doi:10.1002/ajmg.a.30480

Cited by 5 publications

(2 citation statements)

References 23 publications

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“…Clinical genetic evidence supports the viewpoint that chromosome 16p13.11 is a hotspot associated with various neuropsychiatric disorders, such as epilepsy, autism spectrum disorder (ASD), schizophrenia, and attention de cit hyperactivity disorder (ADHD) [1][2][3][4]. Nodal modulator 1 (NOMO1), a negative regulator of the nodal signaling pathway, is located on chromosome 16p13.11.…”

Section: Introductionmentioning

confidence: 95%

Morphological, behavioral and molecular studies on CRISPR/Cas9-mediated knockout of the NOMO1 gene in zebrafish

Lin

et al. 2021

Preprint

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Background: Multiple clinical genome-wide analysis identified that chromosome 16p13.11 is a hotspot associated with neuropsychiatric disorders such as autism, schizophrenia and epilepsy. Nodal modulator 1 (NOMO1), located on human chromosome 16p13.11, was considered as a candidate gene with neuropsychiatric disorders. However, it is unknown whether the nomo1 deficiency causes neurological abnormalities, and the molecular mechanisms and pathogenesis of the NOMO1 gene remain unclear. To study the effects of nomo1 deficiency on brain development and neuropsychiatric system, a nomo1 knockout zebrafish model was established.Methods: We developed a viable vertebrate model of nomo1 loss-of-function using CRISPR/Cas9 technology and characterized nomo1 mutant zebrafish. Phenotypic and functional studies of developing nomo1 mutant zebrafish, including morphological measurements, behavioral assays, and functional mechanistic analyses, were performed.Results: Morphological differences in the phenotype of nomo1-/- zebrafish gradually became less noticeable during development, however, the enlarged interstitial spaces in midbrain and hindbrain were detected in nomo1 mutant zebrafish. Meanwhile, the nomo1 deficiency caused the change of expression levels in neurotransmitters of γ-aminobutyrate, glutamate and serotonin. Interestingly, the nomo1 loss-of-function zebrafish model exhibited social defects and repetitive behaviors in juvenile, which represented autism-like behaviors. The transcriptome analysis showed different gene expression patterns in mutant zebrafish at the genetic level. Further results revealed that the neuroactive drug PTZ recovered the decreased locomotor phenotype in larval mutant zebrafish.Conclusions: In this study, we established a nomo1 vertebrate animal model using CRISPR/Cas9 gene editing approach. The loss-of-function of nomo1 displayed autism-like behaviors and altered levels of the γ-aminobutyrate, glutamate and serotonin in zebrafish, which provide evidence that nomo1 as a candidate gene for autism. The versatility of zebrafish model is contributed to studying NOMO1-related disorders and conducting drug screening in future.Limitations: Further studies are needed to determine whether an intervention with a neuroactive drug in nomo1-/- zebrafish to alter the behavioral phenotype is applicable to the behavior of human patients.

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Section: Introductionmentioning

confidence: 95%

Morphological, behavioral and molecular studies on CRISPR/Cas9-mediated knockout of the NOMO1 gene in zebrafish

Lin

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Clinical genetic evidence supported the viewpoint that chromosome 16p13.11 is a hotspot associated with various neuropsychiatric disorders such as epilepsy, autism spectrum disorder (ASD), schizophrenia, and attention deficit hyperactivity disorder (ADHD) [1][2][3][4]. Nodal modulator 1 (NOMO1), a negative regulator of the Nodal signaling pathway, is located in chromosome 16p13.11.…”

Section: Introductionmentioning

confidence: 99%

Loss-of-function of the NOMO1 Gene Causes Neuropsychiatric Disorder-related Phenotypes

Li¹,

Li²,

Lin³

et al. 2020

Preprint

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Background: Clinical genome-wide analysis identified NOMO1 in human chromosome 16p13.11 as a candidate gene associated with neuropsychiatric disorders such as autism, schizophrenia and epilepsy. However, the important contributions underlying NOMO1 deficiency resulting in neuropsychiatric disorders is not understand, and the molecular and pathogenesis mechanisms of nomo1 gene are unclear. Therefore, it is necessary to construct animal models to systematically study the effects of nomo1 deficiency on neuropsychiatric system and explore pathogenic molecular mechanism of diseases.Methods: We developed a viable vertebrate model of loss-of-function of nomo1 using CRISPR/Cas9 and studied the characterization of nomo1 mutant zebrafish. Phenotypic research was performed in developing nomo1 mutant zebrafish, including morphological measurements, behavioral tests, and functional mechanism analyses.Results: The nomo1 loss-of-function zebrafish model accurately recapitulated key neuropsychiatric disorders traits. The mutant zebrafish showed decreased locomotion in the larval stage (7 dpf), increased spontaneous movement in infancy (15 dpf and 30 dpf), and social defects and repetitive behaviors in adolescence (2 mpf). More importantly, we demonstrated that these behavioral phenotypes stem from abnormal brain structure and neurotransmitter metabolism. Transcriptome analysis provided insights for studying the functional mechanism of nomo1 pathogenesis. Further results revealed that the neuroactive drug PTZ recovered the decreased locomotion phenotype in larval zebrafish, which provides functional basis for the exploration of drug sensitivity and intervention in behavioral phenotypes of nomo1 mutant zebrafish.Conclusion: This study firstly reveal the functional evidence that loss-of-function of nomo1 elicits neuropsychiatric disorders, and emphasize the relationship between nomo1 deficiency and neuropsychiatric disorders from the perspectives of behavioral phenotypes, brain development, and neurotransmitter metabolism.Limitation: The behavioral phenotype intervention of neuroactive drug in nomo1-/-zebrafish can be directly translated to the behavior of human associated diseases need further study.

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Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #1

Zambrano

Wohler

Annerén

et al. 2011

European Journal of Medical Genetics

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A woman with 46,XX,dup(16)(p13.11 p13.3) and the ATR-X phenotype

Cited by 5 publications

References 23 publications

Morphological, behavioral and molecular studies on CRISPR/Cas9-mediated knockout of the NOMO1 gene in zebrafish

Morphological, behavioral and molecular studies on CRISPR/Cas9-mediated knockout of the NOMO1 gene in zebrafish

Loss-of-function of the NOMO1 Gene Causes Neuropsychiatric Disorder-related Phenotypes

Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #1

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