Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics

Malwade, Susmita; Gasthaus, Janina; Bellardita, Carmelo; Andelic, Matej; Moric, Borna; Korshunova, Irina; Kiehn, Ole; Vasistha, Navneet A.; Khodosevich, Konstantin

doi:10.1016/j.biopsych.2021.09.012

Cited by 13 publications

(18 citation statements)

References 72 publications

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“…that the disease-relevant impact of the 15q13.3 microdeletion is probably caused by the combinatorial effects of several genes, rather than a single "master" gene. Our analysis showed network-wide dysregulatory effects and explains why knockout models of singular genes encompassed in the deletion could not fully recapitulate the phenotype [3][4][5][6][7][8][9][10] .…”

Section: Discussionmentioning

confidence: 90%

“…1B) 2 . It is difficult to dissect the mechanisms contributing to the nervous system developmental disturbance mostly because of the limitations of in vitro approaches aiming to reproduce human brain development 10 . Thus, the etiology of the 15q13.3 microdeletion's range of hypervariable symptoms remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…This aligns with experimental data from Df[h15q13]/+ mice, which shows that both loss of OTUD7A and CHRNA7 contribute to dendrite outgrowth defects 3,6 , and also with the recently described involvement of Klf13 in the development of cortical interneurons. 10 To determine whether other DEGs silenced in the adult human brain might have played a role in the nervous system development, we used the Allen Brain Atlas data, which provides brain gene expression data during different developmental stages. 24 This showed that a significant number of genes found to be differentially expressed in blood, but silenced in the adult brain had maximum expression levels in the prenatal stage (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Many functional and association studies inquired which gene(s) encompassed by the deleted region could be responsible for the phenotype. However, the results were as variable as the clinical manifestation and different groups proposed multiple candidates ( CHRNA7 3,4 , OTUD7A 5,6 , FAN1 7 , ARHGAP11B 8 , TRPM1 9 , KLF13 10 ), to explain the symptoms (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

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Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Körner

Velluva

Bundalian

et al. 2022

Preprint

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Background: The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive. Methods: We analyzed gene expression using blood from 3 individuals with 15q13.3 microdeletion and brain cortex tissue from 10 mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein-protein interaction (PPI) functional modules, and gene expression in brain developmental stages. Results: The deleted genes' haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a singular critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development. Conclusions: We show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Körner

Velluva

Bundalian

et al. 2022

Preprint

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“…Given the Ankyrin-G deficits at the AIS and the reduced intrinsic excitability in 15q13.3 microdeletion iNeurons, we speculate that inhibitory synapse formation onto the AIS of excitatory neurons could be a critical site of dysfunction. Other potential contributing genes with evidence for roles in neurodevelopmental phenotypes include FAN1, KLF13, and TRPM1 [130][131][132] . It is also possible that these potential candidate genes may be acting in different cell populations and/or at different time points during brain development.…”

Section: Discussionmentioning

confidence: 99%

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Unda

Chalil

Yoon

et al. 2022

Preprint

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Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

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Duplication Versus Deletion Through the Lens of 15q13.3: Clinical and Research Implications of Studying Copy Number Variants Associated with Neuropsychiatric Disorders in Induced Pluripotent Stem Cell-Derived Neurons

Antony

Narasimhan²,

Shen³

et al. 2022

Stem Cell Rev and Rep

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Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics

Cited by 13 publications

References 72 publications

Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Duplication Versus Deletion Through the Lens of 15q13.3: Clinical and Research Implications of Studying Copy Number Variants Associated with Neuropsychiatric Disorders in Induced Pluripotent Stem Cell-Derived Neurons

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