Mice with mutations in Trpm1, a gene in the locus of 15q13.3 microdeletion syndrome, display pronounced hyperactivity and decreased anxiety-like behavior

Hori, Tesshu; Ikuta, Shohei; Takao, Keizo; Miyakawa, Tsuyoshi; Koike, Chieko

doi:10.1186/s13041-021-00749-y

Cited by 6 publications

(10 citation statements)

References 68 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: 91%

“…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%

“…The color legend corresponds to the pLI score as a measure of loss-of-function deleteriousness 40 . Underlined genes have been considered candidates that are responsible for the observed phenotypes ( CHRNA7 3,4 , OTUD7A 5,6 , FAN1 7 , ARHGAP11B 8 , TRPM1 9 , KLF13 10 ) B. Individuals with 15q13.3 microdeletion display a heterogenous phenotype which can range from normal development to severe intellectual disability (ID) or neurodevelopmental disorders (NDD).…”

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: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…From those, neurodeveland conditions are the predominant features with developmental/learning disabilities being the most commonly reported finding (Lowther et al 2015). Among the genes deleted by this copy number variant, CHRNA7 and TRPM1 are the most likely to be linked with neurological phenotypes (Deutsch et al 2016;Hori et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic findings in TRPM1‐related congenital stationary night blindness

Iosifidis

Liu

Gale

et al. 2022

Acta Ophthalmologica

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Purpose: Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy. Methods: Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis.Results: Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case. Conclusion: Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.

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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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Mice with mutations in Trpm1, a gene in the locus of 15q13.3 microdeletion syndrome, display pronounced hyperactivity and decreased anxiety-like behavior

Cited by 6 publications

References 68 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

Clinical and genetic findings in TRPM1‐related congenital stationary night blindness

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

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