Associations between polymorphisms of LSAMP gene and schizophrenia

Koido, Kati; Janno, Sven; Traks, Tanel; Parksepp, Madis; Ljubajev, Ülle; Veiksaar, Peeter; Must, Anne; Shlik, Jakov; Vasar, Veiko; Vasar, Eero

doi:10.1016/j.psychres.2014.01.016

Cited by 24 publications

(20 citation statements)

References 17 publications

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“…The pivotal connection between CFSs and genomic instability was further underscored by presence of genes involved in different diseases that go from tumorigenesis-most of them tumor-suppressor genes-to psychiatric disorders [77][78][79].…”

Section: Discussionmentioning

confidence: 99%

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Maccaroni

Balzano

Mirimao

et al. 2020

Genes

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Common fragile sites (CFSs) are particularly vulnerable regions of the genome that become visible as breaks, gaps, or constrictions on metaphase chromosomes when cells are under replicative stress. Impairment in DNA replication, late replication timing, enrichment of A/T nucleotides that tend to form secondary structures, the paucity of active or inducible replication origins, the generation of R-loops, and the collision between replication and transcription machineries on particularly long genes are some of the reported characteristics of CFSs that may contribute to their tissue-specific fragility. Here, we validated the induction of two CFSs previously found in the human fetal lung fibroblast line, Medical Research Council cell strain 5 (MRC-5), in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90). After induction of CFSs through aphidicolin, we confirmed the expression of the CFS 1p31.1 on chromosome 1 and CFS 3q13.3 on chromosome 3 in both fetal lines. Interestingly, these sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity. Both these sites contained late-replicating genes NEGR1 (neuronal growth regulator 1) at 1p31.1 and LSAMP (limbic system-associated membrane protein) at 3q13.3, which are much longer, 0.880 and 1.4 Mb, respectively, than the average gene length. Given the established connection between long genes and CFS, we compiled information from the literature on all previously identified CFSs expressed in fibroblasts and lymphocytes in response to aphidicolin, including the size of the genes contained in each fragile region. Our comprehensive analysis confirmed that the genes found within CFSs are longer than the average human gene; interestingly, the two longest genes in the human genome are found within CFSs: Contactin Associated Protein 2 gene (CNTNAP2) in a lymphocytes’ CFS, and Duchenne muscular dystrophy gene (DMD) in a CFS expressed in both lymphocytes and fibroblasts. This indicates that the presence of very long genes is a unifying feature of all CFSs. We also obtained replication profiles of the 1p31.1 and 3q13.3 sites under both perturbed and unperturbed conditions using a combination of fluorescent in situ hybridization (FISH) and immunofluorescence against bromodeoxyuridine (BrdU) on interphase nuclei. Our analysis of the replication dynamics of these CFSs showed that, compared to lymphocytes where these regions are non-fragile, fibroblasts display incomplete replication of the fragile alleles, even in the absence of exogenous replication stress. Our data point to the existence of intrinsic features, in addition to the presence of long genes, which affect DNA replication of the CFSs in fibroblasts, thus promoting chromosomal instability in a tissue-specific manner.

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Section: Discussionmentioning

confidence: 99%

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Maccaroni

Balzano

Mirimao

et al. 2020

Genes

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“…Anti-LSAMP antibodies have been reported to induce aberrant Timm-stained fibers throughout the CA3 region of the hippocampus 25 , and to significantly decrease the outgrowth of dopaminergic neurons towards the habenula 7 . Human genetic studies have found associations between LSAMP allelic polymorphisms and mood dysfunction, panic disorder, male suicide and schizophrenia 26 , 27 , implying its importance in the formation of the brain circuitry. Furthermore, LSAMP deficient mice display hyperactivity in novel environments and reduced anxiety-like behaviors 28 .…”

Section: Discussionmentioning

confidence: 99%

Ectodomain shedding of Limbic System-Associated Membrane Protein (LSAMP) by ADAM Metallopeptidases promotes neurite outgrowth in DRG neurons

Sanz

Ferraro

Girouard

et al. 2017

Sci Rep

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IgLONs are members of the immunoglobulin superfamily of cell adhesion proteins implicated in the process of neuronal outgrowth, cell adhesion and subdomain target recognition. IgLONs form homophilic and heterophilic complexes on the cell surface that repress or promote growth depending on the neuronal population, the developmental stage and surface repertoire of IgLON family members. In the present study, we identified a metalloproteinase-dependent mechanism necessary to promote growth in embryonic dorsal root ganglion cells (DRGs). Treatment of embryonic DRG neurons with pan-metalloproteinase inhibitors, tissue inhibitor of metalloproteinase-3, or an inhibitor of ADAM Metallopeptidase Domain 10 (ADAM10) reduces outgrowth from DRG neurons indicating that metalloproteinase activity is important for outgrowth. The IgLON family members Neurotrimin (NTM) and Limbic System-Associated Membrane Protein (LSAMP) were identified as ADAM10 substrates that are shed from the cell surface of DRG neurons. Overexpression of LSAMP and NTM suppresses outgrowth from DRG neurons. Furthermore, LSAMP loss of function decreases the outgrowth sensitivity to an ADAM10 inhibitor. Together our findings support a role for ADAM-dependent shedding of cell surface LSAMP in promoting outgrowth from DRG neurons.

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“…Lsamp has been shown to be implicated in hippocampal plasticity and adaptation in changing environments (Qui et al, 2010;. Polymorphisms and expressional alterations in the Lsamp gene in humans have been linked to a spectrum of neuropsychiatric disorders (Must et al, 2008;Behan et al, 2009;Koido et al, 2012Koido et al, , 2014 whereas polymorphisms in the Ntm gene have been found to be associated with cognitive functions (Liu et al, 2007) and intelligence (Pan et al, 2010) and expressional alterations in the dorsolateral prefrontal cortex have been found in schizophrenic brains (Karis et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The combined impact of IgLON family proteins Lsamp and Neurotrimin on developing neurons and behavioral profiles in mouse

Singh

Lilleväli

Gilbert

et al. 2018

Brain Research Bulletin

Self Cite

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Cell surface neural adhesion proteins are critical components in the complex orchestration of cell proliferation, apoptosis, and neuritogenesis essential for proper brain construction and behavior. We focused on the impact of two plasticity-associated IgLON family neural adhesion molecules, Neurotrimin (Ntm) and Limbic system associated membrane protein (Lsamp), on mouse behavior and its underlying neural development. Phenotyping neurons derived from the hippocampi of Lsamp, Ntm and LsampNtm mice was performed in parallel with behavioral testing. While the anatomy of mutant brains revealed no gross changes, the Ntm hippocampal neurons exhibited premature sprouting of neurites and manifested accelerated neurite elongation and branching. We propose that Ntm exerts an inhibitory impact on neurite outgrowth, whereas Lsamp appears to be an enhancer of the said process as premature neuritogenesis in Ntm neurons is apparent only in the presence of Lsamp. We also show interplay between Lsamp and Ntm in regulating tissue homeostasis: the impact of Ntm on cellular proliferation was dependent on Lsamp, and Lsamp appeared to be a positive regulator of apoptosis in the presence of Ntm. Behavioral phenotyping indicated test-specific interactions between Lsamp and Ntm. The phenotypes of single mutant lines, such as reduced swimming speed in Morris water maze and increased activity in the elevated plus maze, were magnified in LsampNtm mice. Altogether, evidence both from behavioral experiments and cultured hippocampal cells show combined and differential interactions between Ntm and Lsamp in the formation of hippocampal circuits and behavioral profiles. We demonstrate that mutual interactions between IgLON molecules regulate the initiation of neurite sprouting at very early ages, and even cell-autonomously, independent of their regulation of cell-cell adhesion.

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Associations between polymorphisms of LSAMP gene and schizophrenia

Cited by 24 publications

References 17 publications

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Ectodomain shedding of Limbic System-Associated Membrane Protein (LSAMP) by ADAM Metallopeptidases promotes neurite outgrowth in DRG neurons

The combined impact of IgLON family proteins Lsamp and Neurotrimin on developing neurons and behavioral profiles in mouse

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