Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons

Michelson, Piret; Hartwig, Christina; Schachner, Melitta; Gal, Andreas; Veske, Andres; Finckh, Ulrich

doi:10.1002/humu.9096

Cited by 19 publications

(32 citation statements)

References 36 publications

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“…We interpret these findings as follows: the 200-kDa form is full-length fully glycosylated L1 as described in lysates from whole brain (Faissner et al, 1985;Michelson et al, 2002;Poltorak et al, 1995;Vawter et al, 1998). The protein in this band is immunoreactive with both antibodies to L1CD as well as L1ED, implying the full-length molecule is represented.…”

Section: Discussionmentioning

confidence: 51%

“…However, that form would lack the cytoplasmic domain. Other possibilities include L1 without glycosylation (Michelson et al, 2002) or a proteolytic fragment containing the cytoplasmic domain cleaved by a protease present in adult CSF.…”

Section: Discussionmentioning

confidence: 99%

“…High molecular weight (HMW) bands identified with L1 antibodies are detected in human tissues . These different isoforms may be L1 with immature posttranslational modifications (Faissner et al, 1985;Michelson et al, 2002), or the result of extracellular proteolysis of L1 . These proteolytic fragments may regulate L1 expression and function Michelson et al, 2002;Nayeem et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…These different isoforms may be L1 with immature posttranslational modifications (Faissner et al, 1985;Michelson et al, 2002), or the result of extracellular proteolysis of L1 . These proteolytic fragments may regulate L1 expression and function Michelson et al, 2002;Nayeem et al, 1999). We hypothesized that, in human CSF, there are developmental changes in both the content and the concentration of the HMW isoforms of L1.…”

Section: Introductionmentioning

confidence: 99%

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L1 cell adhesion molecule found in human CSF varies as a function of age

Nock

O’Riordan

Tang

et al. 2006

Experimental Neurology

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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L1 cell adhesion molecule found in human CSF varies as a function of age

Nock

O’Riordan

Tang

et al. 2006

Experimental Neurology

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“…This protein has been shown to be involved in axon guidance and fasciculation, and mutations in this gene reduce or abolish L1-dependent neurite outgrowth in vitro. 18 We observed that plexin B3 is an even more potent stimulator of neurite outgrowth when compared to L1. 8 Therefore, PLXNB3 may be considered an interesting candidate gene for the inborn variability in human-specific cognitive functions and brain volume.…”

Section: Discussionmentioning

confidence: 67%

Plexin B3 is genetically associated with verbal performance and white matter volume in human brain

Rujescu

Krejcova

et al. 2006

Mol Psychiatry

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The presence of genetic influences on cognitive performance and brain volume is well established. However, specific genetic determinants of the variance of these quantitative traits are not yet known. Plexins act as receptors for semaphorins and are implicated in axon guidance, which is a key process in brain development. We have previously shown that plexin B3 is a highly potent stimulator of neurite outgrowth, which makes its gene PLXNB3 an intriguing candidate gene for traits related to human brain development and cerebral connectivity. We identified several polymorphisms in PLXNB3 predicting changes of amino acids (V598I, E1156D and V1596E) conserved at the corresponding positions of the orthologs in mouse and chimpanzee. PLXNB3 was genotyped in 303 healthy volunteers and 42 male patients with schizophrenia. Cognitive performance was measured with the vocabulary test (Wortschatztest (WST)), a method to estimate roughly general intelligence (g). Brain morphology was characterized by magnetic resonance imaging. Compared to subjects not carrying the modern, human-specific haplotype A, carriers of A scored higher in vocabulary test (WST) irrespective of diagnosis (P = 0.0004). This effect could be observed in three independent groups (healthy males: P = 0.048; schizophrenic males: P = 0.034 and healthy females: P = 0.037). Additionally, the haplotype A was associated with increased volume of brain white matter that in turn correlated with performance in the vocabulary test. These findings suggest that plexin B3 may influence cognitive performance, and the development of white matter in vivo in a way similar to its known stimulating effect on neurite outgrowth in vitro. These novel observations warrant further replication in independent samples.

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Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity

Yao,

Qiu,

Wei

et al. 2024

Cell Biochemistry & Function

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L1 syndrome, a neurological disorder with an X‐linked inheritance pattern, mainly results from mutations occurring in the L1 cell adhesion molecule (L1CAM) gene. The L1CAM molecule, belonging to the immunoglobulin (Ig) superfamily of neurocyte adhesion molecules, plays a pivotal role in facilitating intercellular signal transmission across membranes and is indispensable for proper neuronal development and function. This study identified a rare missense variant (c.1759G>C; p.G587R) in the L1CAM gene within a male fetus presenting with hydrocephalus. Due to a lack of functional analysis, the significance of the L1CAM mutation c.1759G>C (p.G587R) remains unknown. We aimed to perform further verification for its pathogenicity. Blood samples were obtained from the proband and his parents for trio clinical exome sequencing and mutation analysis. Expression level analysis was conducted using western blot techniques. Immunofluorescence was employed to investigate L1CAM subcellular localization, while cell aggregation and cell scratch assays were utilized to assess protein function. The study showed that the mutation (c.1759G>C; p.G587R) affected posttranslational glycosylation modification and induced alterations in the subcellular localization of L1‐G587R in the cells. It resulted in the diminished expression of L1CAM on the cell surface and accumulation in the endoplasmic reticulum. The p.G587R altered the function of L1CAM protein and reduced homophilic adhesion capacity of proteins, leading to impaired adhesion and migration of proteins between cells. Our findings provide first biological evidence for the association between the missense mutation (c.1759G>c; p.G587R) in the L1CAM gene and L1 syndrome, confirming the pathogenicity of this missense mutation.

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Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons

Abstract: Mutations in

Cited by 19 publications

References 36 publications

L1 cell adhesion molecule found in human CSF varies as a function of age

L1 cell adhesion molecule found in human CSF varies as a function of age

Plexin B3 is genetically associated with verbal performance and white matter volume in human brain

Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity

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