OBJECTIVE: To analyze the pathogenic variants of the KIF1A gene and its corresponding protein structure in an autism spectrum disorder (ASD) family trio carrying harmful missense variants in the KIF1A gene. METHODS: The peripheral blood DNA of the patient and his parents was extracted and sequenced using whole exome sequencing (WES) technology and verified by Sanger sequencing. Bioinformatics software SIFT, PolyPhen-2, Mutation Taster, and CADD software were used to analyze the harmfulness and conservation of variants. The Human Brain Transcriptome (HBT) database was used to analyze the expression of the KIF1A gene in the brain. PredictProtein and SWISS-MODEL were further used to predict the secondary structure and tertiary structure of KIF1A wild-type protein and variant protein. PyMOL V2.4 was utilized to investigate the change of hydrogen bond connection after protein variant. RESULTS: The WES sequencing revealed a missense variant c.664A>C (p.Asn222His) in the child's KIF1A gene, and this variant was a de novo variant. The harmfulness prediction results suggest that this variant is harmful. By analyzing expression level of KIF1A gene in the brain. It is found that KIF1A gene widely expressed in various brain regions during embryonic development. By analyzing the variant protein structure, the missense variant of KIF1A will cause many changes in the secondary structure of protein, such as alpha-helix, beta-strand, and protein binding domain. The connection of hydrogen bond and spatial structure will also change, thereby changing the original biological function. CONCLUSION The KIF1A gene may be a risk gene for ASD.
Autism Spectrum Disorder/genetics* ; Child ; Female ; Humans ; Kinesin/genetics* ; Mutation ; Mutation, Missense ; Pregnancy ; Protein Domains ; Whole Exome Sequencing

kinesin family member 11 (KIF11) is markedly overexpressed in human breast cancer cells or tissues and positively correlated with distant metastasis and prognosis in patients with breast cancer, suggesting an important role in the regulation of cancer stem cells. Herein, we examined the role of KIF11 in breast cancer stem cells.METHODS: In the current study, we validated our previous findings through analysis of data collected in The Cancer Genome Atlas. Endogenous KIF11 was stably silenced in MCF-7 and SKBR-3 cells. Flow cytometry was used to measure the proportion of side-population (SP) cells. Mammosphere culture and tumor implantation experiments in immunodeficient mice were used to assess the self-renewal ability of breast cancer cells. Real-time polymerase chain reaction, western blot, immunofluorescence staining, luciferase reporter assays and Wnt agonist treatment were conducted to investigate the signaling pathways regulated by KIF11.RESULTS: We found that the expression level of KIF11 was positively correlated with stem cell-enrichment genes. The proportion of SP cells was significantly reduced in KIF11-silenced cells. Silencing endogenous KIF11 not only reduced the size and number of mammospheres in vitro, but also reduced the ability of breast cancer cells to form tumors in mice. Simultaneously, we found that KIF11 was involved in regulating the activation of the Wnt/β-catenin signaling pathway.CONCLUSION: Endogenous KIF11 enhances the self-renewal of breast cancer cells by activating the Wnt/β-catenin signaling pathway, thereby enhancing the characteristics of breast cancer stem cells.]]>
Animals ; beta Catenin ; Blotting, Western ; Breast Neoplasms ; Breast ; Cell Self Renewal ; Flow Cytometry ; Fluorescent Antibody Technique ; Genome ; Humans ; In Vitro Techniques ; Kinesin ; Luciferases ; Mice ; Neoplasm Metastasis ; Neoplastic Stem Cells ; Prognosis ; Real-Time Polymerase Chain Reaction ; Stem Cells

OBJECTIVE: To carry out single nucleotide polymorphism (SNP)-based chromosome microarray analysis (CMA) for a boy featuring global developmental delay. METHODS: The SNP array was conducted for the child, and real-time PCR was used to validate its result and identify the origin of pathological copy number variants. RESULTS: SNP array revealed that the patient has carried a de novo 2.5 Mb duplication at 2q22.3q23.3, which encompassed ACVR2A, KIF5C, MBD5, EPC2, LYPD6, LYPD6, MMADHC and ORC4 genes. Literature review suggested that the MBD5 gene from the duplicated region may have predisposed to the global developmental delay shown by the girl. CONCLUSION The patient's clinical phenotype was consistent to that of 2q23 duplication, for which the MBD5 gene may play a key role. CMA has provided an important tool for the diagnosis of patients with global developmental delay.
Child ; Chromosome Deletion ; Chromosomes, Human, Pair 2 ; DNA Copy Number Variations ; DNA-Binding Proteins ; genetics ; Female ; Genotype ; Humans ; Kinesin ; Phenotype

BACKGROUND/AIMS: The association between the kinesin family member 1B (KIF1B) gene polymorphism and the risk of hepatitis B virus-related hepatocellular carcinoma (HCC) has been investigated in many peer-reviewed studies. However, scholars have failed to replicate these results in validation tests. The purpose of the present study was to explore whether the KIF1B rs17401966 polymorphism was associated with susceptibility to HCC. METHODS: The results of case-controlled studies on the correlation between the KIF1B rs17401966 polymorphism and HCC susceptibility were collected using Google Scholar and the EMBASE, PubMed and CNKI databases. Based on inclusion and exclusion criteria, 5 papers with a total of 12 cohorts were included in this study. RESULTS: The 12 cohorts were integrated, and the results showed that the rs17401966 polymorphism reduced the risk for HCC under the allele, heterozygous, homozygous, and dominant models but not under the additive or recessive models. Moreover, the merged results showed strong heterogeneity, and the cumulative meta-analysis results were unreliable. A genetic differentiation analysis of the 12 cohorts found different degrees of genetic differentiation between the 5 cohorts in Zhang et al.’s study and the cohorts in the other studies. We further divided the 12 study cohorts into 2 subgroups based on fixation index value; however, the results of that analysis were inconsistent. CONCLUSIONS: The results of this meta-analysis were not able to verify the association between the KIF1B rs1740199 polymorphism and HCC risk. Therefore, a well-designed, large-scale, multicenter validation study is needed to confirm the relationship.
Alleles ; Carcinoma, Hepatocellular* ; Case-Control Studies ; Cohort Studies ; Hepatitis B virus* ; Hepatitis B* ; Hepatitis* ; Humans ; Kinesin* ; Polymorphism, Single Nucleotide ; Population Characteristics

OBJECTIVETo explore the expression of KIF18A gene protein in gastric cancer tissues and its association with the prognosis of patients.

METHODSTwenty fresh paired gastric cancer specimens and adjacent normal mucosa(at least 5 cm from the edge of tumor) from 20 gastric cancer patients undergoing operation in Department of General Surgery at the First Affiliated Hosptial of Anhui Medical University between March 2015 and July 2015 were collected. Real-time PCR was used to examine KIF18A mRNA expression in above specimens. Meanwhile, paraffin embedded cancer tissue samples from 129 gastric cancer patients undergoing operation and 23 samples of randomly selected normal gastric tissue(adjacent non-cancer tissue) were collected to establish the microarray. Immunohistochemistry method was applied to detect the KIF18A protein expression in the microarray after confirmation by pathologists. Association of KIF18A expression with clinicopathological features in gastric cancer patients was evaluated. Cox proportional hazard model was used to identify prognostic risk factors.

RESULTSAmong 20 fresh paired gastric cancer specimens, mRNA expression of KIF18A in 16 specimens was obviously lower than that in adjacent normal tissues. The positive rate of KIF18A protein expression in gastric cancer tissues was significantly lower than that in normal gastric tissues in microarray[45.0%(58/129) vs. 69.6%(16/23), P=0.041]. KIF18A protein expression was significantly associated with invasion depth (P=0.008) and TNM staging (P=0.032). The median overall survival of all the 129 patients was 44.0(95% CI: 39.78-49.24) months. The three-year survival rates of patients with high and low KIF18A expression were 67.2% and 36.6% respectively(P=0.020). Cox regression analysis showed that KIF18A expression was an independent protective factor of the prognosis of gastric cancer patients (HR=0.570, 95% CI:0.335 to 0.970).

CONCLUSIONSKIF18A expression is down-regulated in gastric cancer tissue, which may play a critical role in gastric cancer carcinogenesis. Lower expression of KIF18A is associated with poor prognosis of gastric cancer patients. KIF18A may be a potential prognostic marker of gastric cancer.

Biomarkers, Tumor ; metabolism ; Humans ; Immunohistochemistry ; Kinesin ; metabolism ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Stomach Neoplasms ; diagnosis ; metabolism ; Survival Rate

OBJECTIVETo study the relationship between SNP rs17401966 at the KIF1B gene and the genetic susceptibility to Hepatocellular carcinoma (HCC).

METHODSAll study objects were recruited from two Grade A hospitals of Amoy from January 2011 to October 2014.They were surveyed in individual matching case-control study. Accepting criterias in the cases: HCC was first diagnosed based on diagnostic basis during the investigations, over 18 years old, present addresses were as same as surveyed areas in the district (county) level range, no past history of cancers; Exclusion criterias: patients with other liver diseases. The tumor patients without HCC, patients with autoimmune hepatitis or toxic hepatitis, patients who refused to be investigated or too ill to be investigated. Accepting criterias in the controls: the control who passed the physical examination matched the case in ages (no more than 3 years old), sex, health screening in the same hospital over the same period and district (county); Exclusion criterias: people with liver disease or any history of cancers. This study consisted of 376 HCC patients and 403 controls, 5 ml morning fasting venous blood of all subjects were obtained to isolate cells and distribute genotype. The differences in general information between cases and controls were tested by χ² test and t-test. The association between SNP rs17401966 and the risk of developing HCC were assessed by using the multiple factors logistic regression.

RESULTSThe mean age and standard deviation for case and control groups were (61.7 ± 12.8) years and (60.6 ± 12.7) years (t = 1.15, P = 0.251), respectively. The proportion of family history of cancer [28.7% (108/376)] and the HBsAg positive rate [26.9 % (101/376)] in case group were higher than these in control group [15.9% (64/403), 2.7% (11/403)] (χ² = 18.65, 92.02, P < 0.001). In HBsAg carriers, GG genotype genetic susceptibility to HCC is 0.12 (0.02-0.75) times for AA genotype, and G allele susceptibility to HCC is 0.38 (0.15-0.98) times for A allelc. In HBsAg negative group, it showed no statistical significance in the relationship between SNP rs17401966 and susceptibility to HCC, and compared with the A allele, the risk for HCC of G allele is 0.79 (0.62-1.01).

CONCLUSIONThe results demonstrated that the presence of the GG genotype, the GA genotype and the G allele at rs17401966 of the KIF1B gene might decrease the risk for HCC.

Aged ; Alleles ; Carcinoma, Hepatocellular ; Case-Control Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; Kinesin ; Liver Neoplasms ; Middle Aged ; Polymorphism, Single Nucleotide

Although it has been suggested that kinesin family member 14 (KIF14) has oncogenic potential in various cancers, including hepatocellular carcinoma (HCC), the molecular mechanism of this potential remains unknown. We aimed to elucidate the role of KIF14 in hepatocarcinogenesis by knocking down KIF14 in HCC cells that overexpressed KIF14. After KIF14 knockdown, changes in tumor cell growth, cell cycle and cytokinesis were examined. We also examined cell cycle regulatory molecules and upstream Skp1/Cul1/F-box (SCF) complex molecules. Knockdown of KIF14 resulted in suppression of cell proliferation and failure of cytokinesis, whereas KIF14 overexpression increased cell proliferation. In KIF14-silenced cells, the levels of cyclins E1, D1 and B1 were profoundly decreased compared with control cells. Of the cyclin-dependent kinase inhibitors, the p27Kip1 protein level specifically increased after KIF14 knockdown. The increase in p27Kip1 was not due to elevation of its mRNA level, but was due to inhibition of the proteasome-dependent degradation pathway. To explore the pathway upstream of this event, we measured the levels of SCF complex molecules, including Skp1, Skp2, Cul1, Roc1 and Cks1. The levels of Skp2 and its cofactor Cks1 decreased in the KIF14 knockdown cells where p27Kip1 accumulated. Overexpression of Skp2 in the KIF14 knockdown cells attenuated the failure of cytokinesis. On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27Kip1 for degradation by the 26S proteasome, leading to accumulation of p27Kip1. The downregulation of Skp2 and Cks1 also resulted in cytokinesis failure, which may inhibit tumor growth. To the best of our knowledge, this is the first report that has identified the molecular target and oncogenic effect of KIF14 in HCC.
Carcinoma, Hepatocellular/*metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics/*metabolism ; Cyclins/genetics/metabolism ; *Cytokinesis ; Gene Silencing ; Hep G2 Cells ; Humans ; Kinesin/genetics/*metabolism ; Liver Neoplasms/*metabolism ; Oncogene Proteins/genetics/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; RNA, Messenger/genetics/metabolism ; S-Phase Kinase-Associated Proteins/genetics/metabolism ; *Ubiquitination

Rat brain kinesin is a conventional kinesin that uses the energy from ATP hydrolysis to walk along the microtubule progressively. Studying how the chemical energy in ATP is utilized for mechanical movement is important to understand this moving function. The monomeric motor domain, rK354, was crystallized. An ATP analog, AMPPNP, was soaked in the active site. Comparing the complex structure of rK354 x AMPPNP and that of rK354ADP, a hypothesis is proposed that Glu237 in the Switch II region sensors the presence of gamma-phosphate and transfers the signal to the microtubule binding region.
Adenosine Triphosphate ; metabolism ; Adenylyl Imidodiphosphate ; metabolism ; Animals ; Brain ; metabolism ; Catalytic Domain ; Crystallography ; Hydrolysis ; Kinesin ; metabolism ; Microtubules ; metabolism ; Phosphates ; Protein Binding ; Rats

Kinesin is a motor protein that uses the energy from ATP hydrolysis to move along the microtubule system. To investigate how the chemical energy stored in ATP is converted to mechanical movement, the corresponding N-terminal region of rat brain kinesin was expressed in BL21-Codon Plus (DE3)-RP competent cells. After SP-cation exchange chromatography and size exclusion chromatography, the protein yield reached 10 mg/L culture with the purity above 95%. The purified protein had ATPase activity and specifically reacted with the kinesin antibody in the Western blotting analysis. The purified kinesin was crystallized under the following condition: 1.7 mol/L (NH4)2SO4, 500 mmol/L NaCl, 20% glycerol. The kinesin crystal can diffract up to 2.0 angstroms resolution.
Animals ; Brain ; enzymology ; Crystallization ; Hydrolysis ; Kinesin ; chemistry ; isolation & purification ; Rats

The kinesin superfamily is a class of motor proteins moving along microtubule filaments and playing essential roles in mitosis of eukaryotic cells. In the cancer biology, mitotic activity is an essential factor for development and metastasis of various cancers. Therefore, the inhibition of kinesin activity is suggested as an alternative cancer therapy. Accumulated clinical evidences have proved the potency of kinesin inhibitors in cancer treatments. In this review, we provided an overview of kinesins that play a critical role in the pathophysiology of various cancers and described the beneficial vs. side effects of their inhibitors that have been tested in both basic science and clinical studies.
Biology ; Eukaryotic Cells ; Kinesin* ; Microtubules ; Mitosis ; Neoplasm Metastasis ; Translational Medical Research*