Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3

Pfaender, Stefanie; Sauer, Ann Katrin; Hagmeyer, Simone; Mangus, Katharina; Linta, Leonhard; Liebau, Stefan; Bockmann, Juergen; Huguet, Guillaume; Bourgeron, Thomas; Boeckers, Tobias M.; Grabrucker, Andreas M.

doi:10.1038/srep45190

Cited by 54 publications

(65 citation statements)

References 66 publications

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“…Interestingly, all four have been implicated in studies of neuropsychiatric disorders. These genes were CNTN4, a cell adhesion molecule associated with autism [55] and schizophrenia [56]; PCDHGA10, a member of the protocadherin family of cell adhesion proteins which has been implicated in schizophrenia and autism [44]; SLC39A4, a zinc transport protein known to be regulated by SHANK3, a highly penetrant risk factor for autism [57]; and SORCS1, which alters amyloid precursor protein processing and is associated with Alzheimer's disease [58].…”

Section: Correlation and Overlap Analysismentioning

confidence: 99%

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Zhang

et al. 2019

Preprint

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Heterozygous deletions in the 15q13.3 region are associated with several neuropsychiatric disorders including autism, schizophrenia, and attention deficit hyperactivity disorder. Several genes within the 15q13.3 deletion region may play a role in neuronal dysfunction, based on association studies in humans and functional studies in mice, but the intermediate molecular mechanisms remain unknown.We analyzed the genome-wide effects of the 15q13.3 microdeletion on the transcriptome and epigenome. Induced pluripotent stem cell (iPSC) lines from three patients with the typical heterozygous 15q13.3 microdeletion and three sex-matched controls were generated and converted into induced neurons (iNs) using the neurogenin-2 induction method. We analyzed genome-wide gene expression using RNA-Seq, genome-wide DNA methylation using SeqCap-Epi, and genome-wide chromatin accessibility using ATAC-Seq, in both iPSCs and iNs. In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the deletion on the transcriptome and epigenome, with the effects being cell type specific and occurring at discrete loci. Several genes and pathways associated with neuropsychiatric disorders and neuronal development were significantly altered, including Wnt signaling, ribosome biogenesis, DNA binding, and clustered protocadherins. This molecular systems analysis of a large neuropsychiatric microdeletion can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders. IntroductionThe neuropsychiatric 15q13.3 microdeletion (OMIM 612001) is a heterozygous deletion of approximately 1.5-2 Mb at coordinates 30.5 Mb to 32.5 Mb on chromosome 15 (hg19) [1]. The deletion breakpoints lie within two regions of segmental duplications, which likely mediate the creation of the recurrent microdeletion via non-allelic homologous recombination [2]. The 15q13.3 microdeletion has an estimated prevalence of 1 in 40,000 individuals, and was first reported in 2008, in nine individuals with mental retardation, seizures, and mild facial dysmorphism [3]. Since then, several other phenotypes have been associated with this copy number variant (CNV), including autism spectrum disorder, schizophrenia, mood disorders, attention deficit hyperactivity disorder, hypotonia, and cardiac defects [1,4,5].The most common form of the 15q13.3 microdeletion, which is the subject of our study, results in the heterozygous loss of seven protein-coding genes (CHRNA7, FAN1, TRPM1, KLF13, OTUD7A, MTMR10, ARHGAP11B) and one microRNA (MIR211) [4]. Several of these genes have previously been investigated as candidates for having a role in the neuropsychiatric symptoms associated with the CNV. The most frequently proposed candidate gene is C...

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Section: Correlation and Overlap Analysismentioning

confidence: 99%

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Zhang

et al. 2019

Preprint

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“…This leads to synaptic defects and can also lead to autism [94,99]. Moreover, the relation of zinc uptake and the expression of Shank3 regarding autism has been studied recently [100]. This study only included participants with genetically confirmed diagnosis of Phelan McDermid Syndrome (PMDS) with deletion of Shank3 gene [100].…”

Section: Zinc Deficiencymentioning

confidence: 99%

“…Moreover, the relation of zinc uptake and the expression of Shank3 regarding autism has been studied recently [100]. This study only included participants with genetically confirmed diagnosis of Phelan McDermid Syndrome (PMDS) with deletion of Shank3 gene [100]. The study showed that low Shank3 levels resulted in abnormally low zinc transporter, which led to low zinc concentration [100].…”

Section: Zinc Deficiencymentioning

confidence: 99%

“…This study only included participants with genetically confirmed diagnosis of Phelan McDermid Syndrome (PMDS) with deletion of Shank3 gene [100]. The study showed that low Shank3 levels resulted in abnormally low zinc transporter, which led to low zinc concentration [100]. Statistical data also suggests the close relationship between zinc deficiency and infantile autism [101].…”

Section: Zinc Deficiencymentioning

confidence: 99%

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Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Yoon

Choi

Lee

et al. 2020

JCM

105

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Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. Environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to ASD susceptibility. As ASD is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of ASD. Accumulated evidence also shows an important role of epigenetic factors, such as DNA methylation, histone modification, and noncoding RNA, in ASD etiology. In this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of ASD.

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“…Mounting evidence suggests that the released free zinc might contribute to the excitotoxicity of hippocampal neuronal injury aer brain trauma and that the accumulation of Zn 2+ might be part of the mechanism responsible for reduced neuronal survival following injury; however, this hypothesis has not been fully proven yet. 7,[10][11][12][13][14][15] Vesicular free zinc is the only form of zinc which is readily stained and which can be revealed by histochemical techniques with any certainty. 4 Direct histochemical detection of synaptic zinc is difficult and puts high demand on sample preparation and treatment and the small detectable amount of zinc in vesicles in the zinc-containing neurons is only a small fraction of the total zinc in the brain.…”

Section: Introductionmentioning

confidence: 99%