Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population

Liang, Shuang; Wang, Xuelai; Zou, Mingyang; Wang, Han; Zhou, Xue; Sun, Chongde; Xia, Wei; Wu, Lijie; Fujisawa, Takashi; Tomoda, Akemi

doi:10.1631/jzus.b1300133

Cited by 30 publications

(22 citation statements)

References 36 publications

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“…DOCK4 is located at chromosome band 7q31.1 [18,19], an autism-susceptible locus resided by several ASD-associated genes involved in development and language regulation. Recent studies have identified a number of DOCK4 variations associated with ASD, including both single nucleotide variations (SNVs) and chromosome microdeletions or duplications (Supplementary Table 1) [18][19][20][21][22][23][24][25][26]. Many of these variations are believed to result in loss-of-function of DOCK4.…”

Section: Introductionmentioning

confidence: 99%

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

et al. 2019

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Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.

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Section: Introductionmentioning

confidence: 99%

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

et al. 2019

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“…Several data indicate that mutations/deletions of the IMMP2L gene are associated with ASD; however, the existence of such an association is still debated [Petek et al, 2007;Liang et al, 2014]. The notion that IMMP2L alter- ations may predispose to cognitive/behavioral disturbances is supported also by in vivo models: for example, in mice heterozygous for an inactive Immp2l gene, increase of ischemic brain damage and apoptosis of cerebellar neurons have been detected [Ma et al, 2017;Liu et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

“…Several data indicate that alterations of the IMMP2L gene are linked with autism spectrum disorders (ASD) [Petek et al, 2001;Muhle et al, 2004;Maestrini et al, 2010;Casey et al, 2012]. However, this is discussed controversially, since some studies do not support this association [Petek et al, 2007;Liang et al, 2014]. For example, Zhang et al [2018], by performing a trio family study and meta-analysis, found no evidence for an association between IMMP2L gene deletions and ASD.…”

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confidence: 99%

Genomic Deletion Involving the <b><i>IMMP2L</i></b> Gene in Two Cases of Autism Spectrum Disorder

Baldan¹,

Gnan²,

Franzoni

et al. 2018

Cytogenet Genome Res

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Mutations/deletions of the IMMP2L gene have been associated with different cognitive/behavioral disturbances, including autism spectrum disorders (ASD). The penetrance of these defects is not complete since they often are inherited from a healthy parent. Using array-CGH in a cohort of 37 ASD patients, we found 2 subjects harboring a deletion inside the IMMP2L gene. In both cases, the IMMP2L gene deletion was inherited: from a healthy mother in one case and from a dyslectic father in the other. In the latter family, the IMMP2L deletion was also detected in the patient's brother, who showed delayed language development. In a cohort of 100 normal controls, no deletions including the IMMP2L gene were observed. However, a recent meta-analysis found no association between IMMP2L deletions and ASD. Our data would indicate that deletions involving the IMMP2L gene may contribute to the development of a subgroup of cognitive/behavioral disorders.

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“…The complexity arises when we observed independent studies with negative association. Petek et al () and Liang et al () found no evidence of association in their ASD cohort of 95 multiples ASD families and 370 ASD trios in Chinese Han population, respectively.…”

Section: Introductionmentioning

confidence: 92%

Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta‐analysis

Zhang

Liu

Zarrei

et al. 2017

American J of Med Genetics Pt B

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IMMP2L, the gene encoding the inner mitochondrial membrane peptidase subunit 2-like protein, has been reported as a candidate gene for Tourette syndrome, autism spectrum disorder (ASD) and additional neurodevelopmental disorders. Here we genotyped 100 trio families with an index proband with autism spectrum disorder in Han Chinese population and found three cases with rare exonic IMMP2L deletions. We have conducted a comprehensive meta-analysis to quantify the association of IMMP2L deletions with ASD using 5,568 cases and 10,279 controls. While the IMMP2L deletions carried non-recurrent breakpoints, in contrast to previous reports, our metaanalysis found no evidence of association (P > 0.05) between IMMP2L deletions and ASD. We also observed common exonic deletions impacting IMMP2L in a separate control (5,971 samples) cohort where subjects were screened for psychiatric conditions. This is the first systematic review and meta-analysis regarding the effect of IMMP2L deletions on ASD, but further investigations in different populations, especially Chinese population may be still needed to confirm our results. K E Y W O R D Sautism spectrum disorder (ASD), IMMP2L, meta-analysis

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Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population

Cited by 30 publications

References 36 publications

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Genomic Deletion Involving the <b><i>IMMP2L</i></b> Gene in Two Cases of Autism Spectrum Disorder

Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta‐analysis

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