Mouse Models of 22q11.2-Associated Autism Spectrum Disorder

Hiroi, Noboru; Hiramoto, Takeshi; Harper, Kathryn M.; Suzuki, Go; Boku, Shuken

doi:10.4172/2165-7890.s1-001

Cited by 13 publications

(27 citation statements)

References 125 publications

(156 reference statements)

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“…We demonstrated this by systematically altering genetic background in the setting of Sept5 deficiency. 187–189 This modulatory effect of genetic background provides a plausible explanation for the seemingly inconsistent observations that deletion of Prodh or Tbx1 causes PPI deficit in one but not another mouse line with different genetic backgrounds. 145,181,202,203 This hypothesis underscores the necessity to analyze mice under several genetic backgrounds.…”

Section: General Hypothetical Rules Of 22q112 Cnv–phenotype Relationmentioning

confidence: 97%

“…187,188 Moreover, the phenotypic expression of Sept5 deficiency is attenuated or amplified when genetic background is systematically altered. 187–189 As virally guided overexpression of Sept5 alone against a coisogenic genetic background is sufficient to raise social interaction, 187 phenotypic differences between WT and Sept5 -deficient mice do not simply reflect the collective impact of alleles other than Sept 5.…”

Section: Genetic Mouse Models Of Cnvsmentioning

confidence: 99%

“…Although, in some cases, heterozygosity was not and homozygosity was sufficient to cause a specific phenotype in mice (e.g., Sept5 and Zdhhc8 ), 188,197 the mechanism by which gene-dose alteration causes a phenotype depends on genetic background, 187–189 which is not identical in humans and mice.…”

Section: Genetic Mouse Models Of Cnvsmentioning

confidence: 99%

“…145,181,202,203 This hypothesis underscores the necessity to analyze mice under several genetic backgrounds. 187–189 …”

Section: General Hypothetical Rules Of 22q112 Cnv–phenotype Relationmentioning

confidence: 99%

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Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

et al. 2013

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Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders.

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Section: General Hypothetical Rules Of 22q112 Cnv–phenotype Relationmentioning

confidence: 97%

Section: Genetic Mouse Models Of Cnvsmentioning

confidence: 99%

Section: Genetic Mouse Models Of Cnvsmentioning

confidence: 99%

“…145,181,202,203 This hypothesis underscores the necessity to analyze mice under several genetic backgrounds. 187–189 …”

Section: General Hypothetical Rules Of 22q112 Cnv–phenotype Relationmentioning

confidence: 99%

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Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

et al. 2013

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“…Also, 12 additional T-Box1 (TBX1) probes are included in the P324 kit (the P250 kit has only two TBX1 probes) (supplementary on-line material, table 1). TBX1 is one of the most important candidate genes at 22q11.2 concerning physical abnormalities in 22q11DS [30, 31], but it is also associated with psychiatric features like autism spectrum disorders [32] and in mouse models with social interaction problems [33] and autism [34]. …”

Section: Introductionmentioning

confidence: 99%

The use of two different MLPA kits in 22q11.2 deletion syndrome

Evers

Engelen

Houben

et al. 2016

European Journal of Medical Genetics

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22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other “typical ones”. We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis.

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Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

Zhao

Guo

Fiksinski

et al. 2018

American J of Med Genetics Pt A

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The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46) and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (P = 0.002), verbal IQ was decreased by 8.17 points (P = 0.0002) and performance IQ was decreased by 4.03 points (P = 0.028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explain the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

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Mouse Models of 22q11.2-Associated Autism Spectrum Disorder

Cited by 13 publications

References 125 publications

Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

The use of two different MLPA kits in 22q11.2 deletion syndrome

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

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