Analysis of a pedigree affected with HSAS syndrome due to a noval variant of L1CAM gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with hydrocephalus.@*METHODS@#The fetus was found to have hydrocephalus upon ultrasonography duringthe second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA and whole exome sequencing.Sanger sequencing was used to verify the suspected variants in the family.@*RESULTS@#The fetus was found to harbor a hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene (OMIM 308840),for which his mother and sister were heterozygous carriers. The same variant was not found in his father, uncle and grandparents.Based on the standards and guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PM1+PM2+PP3+PP4).@*CONCLUSION@#The hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene probably underlay the hydrocephalus in this fetus.

Analysis of L1CAM gene mutation in pedigrees with X-linked genetic hydrocephalus / 中华医学遗传学杂志

OBJECTIVE@#To analyze L1CAM gene mutation in a family featuring X-linked recurrent fetal hydrocephalus.@*METHODS@#The family had three pregnancies where a male fetus was detected at 22 weeks with hydrocephalus by ultrasonography. DNA was extracted from peripheral blood samples from the parents as well as fetal tissue from the third abortion. The fetal DNA was subjected to testing of folic acid metabolism ability gene and chromosomal microarray analysis (CMA). Next-generation sequencing (NGS) was employed to detect potential mutation of related genes. Suspected mutation was verified by Sanger sequencing.@*RESULTS@#Testing of folic acid metabolism ability gene (MTHFR C677T) and CMA were both normal. A c.512G>A (p.Trp171Ter) hemizygous mutation of the L1CAM gene was detected in the fetal tissue, which was inherited from the phenotypically normal mother. The novel mutation was predicted to be pathogenic.@*CONCLUSION@#The c.512G>A (p.Trp171Ter) mutation of the L1CAM gene probably underlies the X-linked hydrocephalus in this family. Screening of L1CAM gene variations should be carried out for couples experiencing recurrent fetal hydrocephalus affecting the male gender.

Diagnosis of a fetus with X-linked hydrocephalus due to mutation of L1CAM gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a case of recurrent fetal congenital hydrocephalus.@*METHODS@#Next-generation sequencing was carried out for the fetus, the gravida and two of her sisters.@*RESULTS@#The fetus was found to harbor a c.1765T>C (p.Tyr589His) mutation in exon 14 of the L1CAM gene, which was derived from the gravida.@*CONCLUSION@#Male fetuses with recurrent hydrocephalus should be subjected to testing of the L1CAM gene to facilitate genetic counseling and prenatal diagnosis.

Aggressive Supratentorial Ependymoma, RELA Fusion-Positive with Extracranial Metastasis: A Case Report

Ependymoma is the third most common pediatric primary brain tumor. Ependymomas are categorized according to their locations and genetic abnormalities, and these two parameters are important prognostic factors for patient outcome. For supratentorial (ST) ependymomas, RELA fusion-positive ependymomas show a more aggressive behavior than YAP1 fusion-positive ependymomas. Extracranial metastases of intra-axial neuroepithelial tumors are extremely rare. In this paper, we report a case of aggressive anaplastic ependymoma arising in the right frontoparietal lobe, which had genetically 1q25 gain, CDKN2A homozygous deletion, and L1CAM overexpression. The patient was a 10-year-old boy who underwent four times of tumor removal and seven times of gamma knife surgery. Metastatic loci were scalp and temporalis muscle overlying primary operation site, lung, liver, buttock, bone, and mediastinal lymph nodes. He had the malignancy for 10 years and died. This tumor is a representative case of RELA fusion-positive ST ependymoma, showing aggressive behavior.

Promotion of compound fujian tablet on the motor function rehabilitation and neurotization in rats with cerebral infarction / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effects of Compound Fujian Tablet (FJT)on the neurotization in the cerebral infarction rats and to explore its mechanisms for promoting the motor skills.</p><p><b>METHODS</b>Totally 90 Wistar rats were randomly divided into the drug group, the model group, and the sham-operation group, 30 in each group. The rat model of middle cerebral artery occlusion (MCAO) was successfully established by electrocoagulation. Six hours after successful modeling, the rats of the drug group were orally administered with 9 g/kg FJT water solution, and the other groups were orally administered with equal volume of normal saline, once a day for two weeks. The motor skills of rats were examined by beam walking test. The expressions of nestin, polysialic acid neural cell adhesion molecule (PSA-NCAM), microtubule-associated protein 2 (MAP-2), growth-associated protein (GAP-43), and synaptophysin (Syn) in the brain tissue around the infarction were observed by in immunohistochemical assay. The mean staining gray or the optical density value were detected.</p><p><b>RESULTS</b>The 86 rats were recruited in the result analysis. After two weeks of administration, the neural function scoring was obviously higher in the drug group than in the model group with statistical difference (P < 0.01). The expressions of nestin, PSA-NCAM, MAP-2, GAP-43, and Syn in the brain tissue around the infarction were more obviously enhanced in the drug group than in the model group, showing statistical difference (P < 0.01).</p><p><b>CONCLUSION</b>FJT can promote neurotization and improve the motor skill recovery after cerebral infarction.</p>

Aberrant L1 Cell Adhesion Molecule Expression in Cancer: In View of Proliferation, Migration and Invasion / 대한갑상선학회지

L1 cell adhesion molecule (L1CAM) is a 220-kDa type I membrane glycoprotein and is normally expressed in neuronal cells, endothelial cells, and renal epithelial cells. Recent clinical studies demonstrated aberrant L1CAM expression in various cancers, especially at the invasive area of cancers. L1CAM has a key role in tumorigenesis, tumor invasion, and it is associated with a poor prognosis of cancer. Anaplastic thyroid carcinoma (ATC) has a highly poor outcome and it is resistant to conventional treatment. In this review, I discuss the biological role of L1CAM in proliferation, migration, and invasion in the ATC.

Homophilic interaction of the L1 family of cell adhesion molecules

Homophilic interaction of the L1 family of cell adhesion molecules plays a pivotal role in regulating neurite outgrowth and neural cell networking in vivo. Functional defects in L1 family members are associated with neurological disorders such as X-linked mental retardation, multiple sclerosis, low-IQ syndrome, developmental delay, and schizophrenia. Various human tumors with poor prognosis also implicate the role of L1, a representative member of the L1 family of cell adhesion molecules, and ectopic expression of L1 in fibroblastic cells induces metastasis-associated gene expression. Previous studies on L1 homologs indicated that four N-terminal immunoglobulin-like domains form a horseshoe-like structure that mediates homophilic interactions. Various models including the zipper, domain-swap, and symmetry-related models are proposed to be involved in structural mechanism of homophilic interaction of the L1 family members. Recently, cryo-electron tomography of L1 and crystal structure studies of neurofascin, an L1 family protein, have been performed. This review focuses on recent discoveries of different models and describes the possible structural mechanisms of homophilic interactions of L1 family members. Understanding structural mechanisms of homophilic interactions in various cell adhesion proteins should aid the development of therapeutic strategies for L1 family cell adhesion molecule-associated diseases.

An immunohistochemical study on the initial development of 155 kd neurofascin in rat sciatic nerve / 대한수의학회지

Neurofascin, one of the members of L1CAM, has been known to have some important roles during the development of nerve fibers. In order to investigate the role of neurofascin associated with the development of nerve fibers in the rat sciatic nerve, the initial development of NF155 in the paranode was studied with immuno-fluorescence and immuno-electron microscopy. The result of the present study showed NF155 was not detected in the fetal sciatic nerve and began to reveal at the postnatal day 0 (P0) and dramatically increased by time lapse until postnatal day 7 (P7). NF155 was prominently localized in the axolemma of paranode and not detected in the central region of node of Ranvier. According to the present study, NF155 is likely to have some relationships with the formation of paranode and myelin sheath.

A chimeric antibody to L1 cell adhesion molecule shows therapeutic effect in an intrahepatic cholangiocarcinoma model

Intrahepatic cholangiocarcinoma (ICC), a malignant tumor derived from the intrahepatic bile duct epithelium, has a poor prognosis and is refractory to conventional chemotherapy and radiation therapy. Thus, there is an urgent need to develop new effective therapeutic strategies for this disease. We previously found that L1 cell adhesion molecule (L1CAM) plays an important role in tumor progression of ICC, and we generated a murine mAb, A10-A3 (IgG1), that binds to the Ig1 domain of L1CAM. In the present study, we further characterized A10-A3, constructed a chimeric A10-A3 antibody (cA10-A3) containing the constant regions of human IgG1, and evaluated the therapeutic potential in a human ICC xenograft nude mice model. The affinities (K D) of A10-A3 and cA10-A3 for soluble L1CAM were 1.8 nM and 1.9 nM, respectively, as determined by competition ELISA. A10-A3 inhibited L1CAM homophilic binding and was slowly internalized into the tumor cells, but it did not significantly inhibit proliferation of ICC cells in vitro. cA10-A3 mediated antibody-dependent cell-mediated cytotoxicity in vitro and displayed anti-tumor activity in the ICC animal model. These results suggest that the humanized A10-A3 antibody may have potential as an anticancer agent for the treatment of ICC.

Establishment of NCAM L1 minigene model and its splicing patterns in different cell lines / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To establish a minigene model of neural cell adhesion molecule L1 (NCAM L1) gene and to study its splicing patterns in different cell lines.</p><p><b>METHODS</b>Using human genetic cDNA as template, the NCAM L1 minigene fragment was amplified and inserted into eukaryotic expression vector. The minigene was transfected into 4 cell lines and the splicing patterns of NCAM L1 minigene in these cell lines were studied.</p><p><b>RESULTS</b>The splicing patterns of NCAM L1 minigene were different in individual cell lines. In PFSK and Hela cell lines, two splicied isoforms were generated but in COS-1 and R28 cell lines, only one isoform existed.</p><p><b>CONCLUSION</b>NCAM L1 minigene model can be used in alternative splicing analysis.</p>

Neurogenesis by activation of inherent neural stem cells in the rat hippocampus after cerebral infarction / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the changes of neural stem cells (NSCs) in the rat hippocampus after cerebral infarction (CI) and to evaluate the neurogenesis caused by the activation of NSCs.</p><p><b>METHODS</b>CI models of rats were made and rats were assigned to 6 groups: sham-operated, 1 day, 3 days, 7 days, 14 days, and 28 days after CI. The dynamic expression of bromodeoxyuridine (BrdU), polysialylated neural cell adhesion molecule (PSA-NCAM), glial fibrillary acidic protein (GFAP), and neuronal nuclear antigen (NeuN) were determined by immunohistochemistry and immunofluorescence staining. BrdU was used to mark the proliferated NSCs. PSA-NCAM was used to mark the plasticity of activated NSCs. GFAP and NeuN were used to mark the differentiated NSCs.</p><p><b>RESULTS</b>Compared with the controls, the number of BrdU+ cells in the hippocampus increased significantly at 1 day after CI (P < 0.05), reached peak at 7 days after CI (P < 0.05), decreased but still elevated compared with the controls at 14 days after CI (P < 0.05), and nearly unchanged at 28 days after CI. The number of BrdU+/PSA-NCAM+ cells increased significantly at 7 days after CI (P < 0.05), reached peak at 14 days after CI (P < 0.05), and decreased but still elevated compared with the controls at 28 days after CI (P < 0.05). The number of BrdU+/PSA-NCAM+ cells was equal to 60% of the number of BrdU+ cells in all the same period. The number of BrdU+/NeuN+ cells in the hippocampus increased significantly at 14 days after CI (P < 0.05) and reached peak at 28 day after CI (P < 0.05). The number of BrdU+/GFAP+ cells in the hippocampus nearly unchanged after CI.</p><p><b>CONCLUSION</b>CI can stimulate the proliferation of inherent NSCs, and most proliferated NSCs may differentiate into neurons and represent neural plasticity.</p>

Effects of fluoride on neural cell adhesion molecules mRNA and protein expression levels in primary rat hippocampal neurons / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of fluoride on the growth and viability, and mRNA and protein expression levels of neural cell adhesion molecules (NCAM) in primary rat hippocampal neurons.</p><p><b>METHODS</b>The growth and development, the rate of cell survivor, and the mRNA and protein expression levels of NCAM were measured by MTT, RT-PCR, and Western blot respectively after the hippocampal neurons were incubated with 20, 40, and 80 microg/ml sodium fluoride for 24 hours in vitro.</p><p><b>RESULTS</b>As compared with the control group, the number of cells, the length and number of neuritis, and rate of cell survivor were significantly decreased in 80 microg/ml fluoride-treated group (P < 0.05). The mRNA expression levels of NCAM in 40 and 80 microg/ml fluoride-treated groups were significantly lower than that in the control group and decreased with the increasing fluoride concentration. Compared with the control group, the mRNA expression level of NCAM in 20 microg/ml fluoride-treated group was decreased, but the difference was not statistically significant (P > 0.05). The NCAM-180 protein expression levels in 40 and 80 microg/ml fluoride-treated groups, the NCAM-140 protein expression levels in all fluoride-treated groups, and NCAM-120 protein expression level in 80 microg/ml fluoride-treated group were significantly lower than those in the control group (P < 0.05, P < 0.05, P < 0.05, respectively).</p><p><b>CONCLUSION</b>Fluoride might restrain the growth and survival of rat hippocampal neurons, and decrease mRNA and protein expression levels of NCAM. The impairment of developmental hippocampus might be one of the neurotoxicant target sites for fluoride toxicity.</p>

Experimental study on plasticity of proliferated neural stem cells in adult rats after cerebral infarction / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate whether there is endogenous neural stem cell proliferation and whether these proliferated neural stem cells represent neural plasticity in the adult rats after cerebral infarction.</p><p><b>METHODS</b>Cerebral infarction models of rats were established and the dynamic expression of bromodeoxyuridine (BrdU), BrdU/polysialylated neural cell adhesion molecule (PSA-NCAM) were determined by immunohistochemistry and immunofluorescence staining. BrdU was used to mark dividing neural stem cells. PSA-NCAM was used to mark the plasticity of neural stem cells.</p><p><b>RESULTS</b>Compared with controls, the number of BrdU-positive cells in the subventricular zone (SVZ) and hippocampus increased significantly at 1st day after cerebral infarction (P < 0.05), reached maximum at 7th day, decreased markedly at 14th day, but it was still elevated compared with that of the controls (P < 0.05). The number of BrdU-labeled with PSA-NCAM-positive cells increased significantly at 7th day (P < 0.05), reached maximum at 14th day, markedly decreased at 28th day, but it was still elevated compared with that of the controls (P < 0.05). It was equal to 60% of the number of BrdU-positive cells in the same period.</p><p><b>CONCLUSION</b>Cerebral infarction may stimulate the proliferation of endogenous neural stem cells in situ and most proliferated neural stem cells represent neural plasticity.</p>

Experimental study on the proliferation and plasticity of neural stem cells in situ in adult rats after cerebral infarction / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the proliferation and plasticity of neural stem cells in situ in adult rats after cerebral infarction.</p><p><b>METHODS</b>Cerebral infarction models of rats were made and the dynamic expression of bromodeoxyuridine (BrdU) and BrdU/polysialylated neural cell adhesion molecule (PSA-NCAM) were determined by immunohistochemistry and immunofluorescence staining.</p><p><b>RESULTS</b>Compared with the controls, the number of BrdU-positive cells in the subventricular zone (SVZ) and hippocampus increased strikingly at day 1 (P < 0.05), reached maximum at day 7, and decreased markedly at day 14, but it was still elevated compared with that of the controls (P < 0.05); The number of BrdU-labeled with PSA-NCAM-positive cells increased strikingly at day 7 (P < 0.05), reached maximum at day 14, and markedly decreased at day 28, but it was still elevated compared with that of the controls (P < 0.05), and was equal to 60% of the number of BrdU-positive cells in the same period.</p><p><b>CONCLUSIONS</b>Our results indicate that cerebral infarction stimulate the proliferation of inherent neural stem cells in situ and most proliferated neural stem cells represent neural plasticity.</p>