Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Marx, M P; Diestel, Simone; Bozon, Muriel; Keglowich, Laura; Drouot, Nathalie; Bouché, Elisabeth; Frébourg, Thierry; Minz, Marie; Saugier-Veber, Pascale; Castellani, Valérie; Schäfer, Michael K. E.

doi:10.1007/s10048-011-0307-4

Cited by 14 publications

(10 citation statements)

References 50 publications

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“…We also used ConSurf server; the nsSNPs that are located at highly conserved amino acid positions tend to be more deleterious than nsSNPs that are located at non-conserved sites. (supplemental figure 4 for ConSurf result, which is available at https://www.biorxiv.org/ ) There were some studies that have been reported which show pathogenic nsSNPs that cause L1 syndrome (11,(70)(71)(72)(73)(74)(75)(76)(77)(78), which is corresponding with our results. It has been observed that L1CAM polymorphisms are associated in several types of human cancers 79).…”

Section: Discussionsupporting

confidence: 90%

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

Murshed¹,

Mustafa²,

Abdelmoneim³

et al. 2019

Preprint

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Background: Mutations in the human L1CAM gene cause a group of neurodevelopmental disorders known as L1 syndrome (CRASH syndrome). The L1CAM gene provides instructions for producing the L1 protein, which is found all over the nervous system on the surface of neurons. L1 syndrome involves a variety of characteristics but the most common characteristic is muscle stiffness. Patients with L1 syndrome can also suffer from difficulty speaking, seizures, and underdeveloped or absent tissue connecting the left and right halves of the brain. Method: The human L1CAM gene was studied from dbSNP/NCBI, 1499 SNPs were Homo sapiens; of which 450 were missense mutations. This selected for Comprehensive bioinformatics analysis by several in silico tools to investigate the effect of SNPs on L1CAM protein's structure and function. Results: 34 missense mutations (26 novel mutations) out of 450 nsSNPs that are found to be the most deleterious that effect on the L1CAM structural and functional level. Conclusion: Better understanding of L1 syndrome caused by mutations in L1CAM gene was achieved using Comprehensive bioinformatics analysis. These findings describe 35 novel L1 mutations which improve our understanding on genotype-phenotype correlation. And can be used as diagnostic markers for L1 syndrome and besides in cancer diagnosis specifically in breast cancer.

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Section: Discussionsupporting

confidence: 90%

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

Murshed¹,

Mustafa²,

Abdelmoneim³

et al. 2019

Preprint

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“…Co-expression of pEGFP was observed in at least 80–90% of NEGR1-positive cells in all experiments and conditions (data not shown). Cell aggregation assay was essentially performed as described [53] and quantified by determining the increase of average areas of green fluorescent cells and aggregates between 0 min (t1) and 60 min (t2) in each condition using Image J software. The calculated t2/t1 ratios were expressed relative to control cells expressing pEGFP alone.…”

Section: Methodsmentioning

confidence: 99%

Functional Inactivation of the Genome-Wide Association Study Obesity Gene Neuronal Growth Regulator 1 in Mice Causes a Body Mass Phenotype

et al. 2012

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To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control.

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“…Cell culture, immunocytochemistry, and immunoblotting NSC-34 cells were cultured and transfected using polyethylenimine (Marx et al 2012). hemagglutinin (HA)-tagged HIF-1a expression constructs (pcDNA3-HIF-1a-827 and pcDNA3-HIF-1a-736), and the hypoxia response elements (HRE) firefly luciferase reporter plasmid were previously described (Gothi e et al 2000;Arsham et al 2002).…”

Section: Gene Expression Analysismentioning

confidence: 99%

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Schaible

Windschügl

Bobkiewicz

et al. 2014

Journal of Neurochemistry

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HIF-1a is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1a may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1a-dependent response, and alternative splicing in exon 14 of HIF-1a (HIF-1aΔEx14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1a target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1aΔEx14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1aΔEx14 were impaired compared to full-length HIF-1a, but no effects on nuclear translocation of the transcriptional complex partner HIF-1b were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1aΔEx14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1a-dependent response contributes to the neuroprotective effects of 2ME2. Keywords: 2-methoxyestradiol, alternative splicing, cerebral ischemia, HIF-1, neuroprotection, traumatic brain injury.

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Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Cited by 14 publications

References 50 publications

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

Functional Inactivation of the Genome-Wide Association Study Obesity Gene Neuronal Growth Regulator 1 in Mice Causes a Body Mass Phenotype

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

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