Lafora disease (LD) is an autosomal recessive, progressive form of myoclonus epilepsy which affects worldwide. LD occurs mainly in countries like southern Europe, northern Africa, South India, and in the Middle East. LD occurs with its onset mainly in teenagers and leads to decline and death within 2 to 10 years. The genes EPM2A and EPM2B are commonly involved in 90 % of LD cases. EPM2A codes for protein laforin which contains an amino terminal carbohydrate binding module (CBM) belonging to the CBM20 family and a carboxy terminal dual specificity phosphatase domain. Mutations in laforin are found to abolish glycogen binding and have been reported in wet lab methods. In order to investigate on structural insights on laforin mutation K81A, we performed molecular dynamics (MD) simulation studies for native and mutant protein. MD simulation results showed loss of stability due to mutation K87A which confirmed the structural reason for conformational changes observed in laforin. The conformational change of mutant laforin was confirmed by analysis using root mean square deviation, root mean square fluctuation, solvent accessibility surface area, radius of gyration, hydrogen bond, and principle component analysis. Our results identified that the flexibility of K87A mutated laforin structure, with replacement of acidic amino acid to aliphatic amino acid in functional CBM domain, have more impact in abolishing glycogen binding that favors LD.
Matched MeSH terms: Protein Tyrosine Phosphatases, Non-Receptor/genetics*; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Protein Tyrosine Phosphatases, Non-Receptor/chemistry*
Mutations in human laforin lead to an autosomal neurodegenerative disorder Lafora disease. In N-terminal carbohydrate binding domain of laforin, two mutations W32G and K87A are reported as highly disease causing laforin mutants. Experimental studies reported that mutations are responsible for the abolishment of glycogen binding which is a critical function of laforin. Our current computational study focused on the role of conformational changes in human laforin structure due to existing single mutation W32G and prepared double mutation W32G/K87A related to loss of glycogen binding. We performed 10 ns molecular dynamics (MD) simulation studies in the Gromacs package for both mutations and analyzed the trajectories. From the results, the global properties like root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and hydrogen bonds showed structural changes in atomic level observed in W32G and W32G/K87A laforin mutants. The conformational change induced by mutants influenced the loss of the overall stability of the native laforin. Moreover, the change in overall motion of protein was analyzed by principal component analysis and results showed protein clusters expanded more than native and also change in direction in case of double mutant in conformational space. Overall, our report provides theoretical information on loss of structure-function relationship due to flexible nature of laforin mutants. In conclusion, comparative MD simulation studies support the experimental data on W32G and W32G/K87A related to the lafora disease mechanism on glycogen binding.
Matched MeSH terms: Protein Tyrosine Phosphatases, Non-Receptor/genetics*; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Protein Tyrosine Phosphatases, Non-Receptor/chemistry*
Lafora progressive myoclonus epilepsy, also known as Lafora disease (LD), is the most severe and fatal form of progressive myoclonus epilepsy with its typical onset during the late childhood or early adolescence. LD is characterized by recurrent epileptic seizures and progressive decline in intellectual function. LD can be caused by defects in any of the two known genes and the clinical features of these two genetic groups are almost identical. The past one decade has witnessed considerable success in identifying the LD genes, their mutations, the cellular functions of gene products and on molecular basis of LD. Here, we briefly review the current literature on the phenotype variations, on possible presence of genetic modifiers, and candidate modifiers as targets for therapeutic interventions in LD.
Matched MeSH terms: Protein Tyrosine Phosphatases, Non-Receptor/genetics*; Protein Tyrosine Phosphatases, Non-Receptor/metabolism
The invasion of cancer cells into the peritumoral, lymph node and perineural system could be detrimental
on cancer patients. In colorectal cancer (CRC) patients, the presence of lymphovascular (LVI) and/or
perineural (PNI) invasion could significantly influence on the survival rates, treatment options and
recurrence tendencies. To date, no study has analyzed the molecular profile of the concomitant existence of
LVI and PNI in CRC. Here, we reanalyzed The Cancer Genome Atlas (TCGA) CRC datasets and focused
on cases where the information regarding LVI and PNI are available (n=176). We performed differential
gene expression, methylation and microRNA analysis by comparing the groups having both or either LVI
and PNI with the control group (LVI negative and PNI negative). Although there was no significant
difference in the methylation and miRNA profiles, we identified a number of differentially expressed genes
(DEGs). The comparison between the LVI+PNI+ and LVI-PNI- groups revealed key DEGs including
SFTA2, PHACTR3, CRABP2, ODZ3, GRP, HAP1, CSDC2, TMEM59L and HDAC9. Meanwhile, in the
LVI-PNI+ vs LVI-PNI- group, some of the DEGs found were PTPRR, EFNA2, FGF20, IGFL4, METRN
and IGFBPL1. We believe that this study could be beneficial and add value to further understand the
complex molecular profiles of CRC.
Matched MeSH terms: Receptor-Like Protein Tyrosine Phosphatases, Class 7
In this paper, the islet autoimmunity status and relation to clinical characteristics, beta cell function and cardio-metabolic risk factors in young-onset Asian diabetic patients are evaluated at baseline. The study population consisted of 912 patients (from China, India, Malaysia and Singapore) with age 12-40 years and diabetes duration <12 months. Autoantibodies to glutamic acid decarboxylase (GADA) and tyrosine phosphatase (IA-2A), beta cell function and cardio-metabolic risk parameters were assessed. Among our young patient cohort, 105 (11.5%) patients were GADA and/or IA-2A positives (Ab +ve). Ab +ve patients were younger, leaner, had more severe hyperglycaemia and lower beta cell function. The frequency of metabolic syndrome was significantly lower in Ab +ve patients (27%) compared to Ab -ve patients (54%). However, a substantial proportion of patients in both groups of patients had atherogenic dyslipidaemia, hypertension and albuminuria (micro or macro). In our study cohort, only one in 10 Asian youth with new-onset diabetes had evidence of islet autoimmunity. At least 60% of Ab +ve and 50% of Ab -ve patients demonstrated classical features of type 1 and type 2 diabetes respectively. Regardless of autoimmunity status, the cardio-metabolic risk factors, in particular atherogenic dyslipidaemia, hypertension and albuminuria were common in our patients with young-onset diabetes.
Matched MeSH terms: Protein Tyrosine Phosphatases/immunology
This study determined the prevalence and significance of autoantibodies to GAD65 (GAD Ab), insulin (IAA), tyrosine-like phosphatase (IA2) and islet-cell (ICA) in a group of 213 young Malaysian Type 1 diabetics, diagnosed before the age of 40 years. Venous blood was taken at fasting, and at 6 minutes post-glucagon (1 mg i.v.). IAA was detected in 47.4%, GAD Ab in 33.8%, IA2 in 8.9% and ICA in 1.4% of the subjects. When based on post-glucagon C-peptide level of 600 pmol/L, 172 (80.7%) patients had inadequate pancreatic reserve, while the remainder 41(19.3%) showed normal response. The autoantibodies, either alone or in combination, were detectable in both groups of patients; higher prevalence in those with poor or no beta-cell function (73.3% versus 46.3%, p = 0.0001). Although the prevalence of GAD Ab was highest in newly diagnosed patients (< 5 years), unlike IA2 and ICA, the marker remained detectable in 24-25% of those patients with long-standing disease. Nineteen patients could probably belong to the "latent autoimmune diabetes in adults (LADA)" subset, where pancreatic reserve was adequate but patients had detectable autoantibodies and insulin-requiring. On the other hand, 68 of the 213 patients (32%) were seronegative, but presented with near or total beta-cell destruction. Thus, as has also been suggested by others, there is indeed etiological differences between the Asian and the Caucasian Type 1 diabetics, and, there is also the possibility that other, but unknown autoantigens are involved in causing the pancreatic damage.
Matched MeSH terms: Protein Tyrosine Phosphatases/immunology
Pre-menopausal women have a lower risk of cardiovascular disease compared to post-menopausal women. Cardiovascular disease is more age dependent in women than in men. The association of platelet activation and cardiovascular thrombotic events is well established. Standardized techniques were used to evaluate platelet activation markers by flow cytometry, using 3-color analysis (CD 61PerCP, CD 62P, and PAC-1) in 49 post-menopausal (mean +/- SD age, 56.16 +/- 33.51 years) and 42 pre-menopausal (age, 39.38 +/- 7.07 years) women. Results of our study showed a significant increase in CD 62P in post-menopausal women as compared to the pre-menopausal group (2.66 +/- 4.26% vs. 0.52 +/- 2.71%, P < 0.001). Similarly, PAC-1 was significantly increased in post-menopausal women (21.54 +/- 2.48% vs. 3.70 +/- 2.31%, P < 0.001). Furthermore, there was a significant association of CD 62P with serum estradiol in both groups. PAC-1 was significantly associated with age in both groups. The results suggest the role of platelets in the increased incidence of thrombotic events and disease in post-menopausal women.
Matched MeSH terms: Protein Tyrosine Phosphatases/biosynthesis
Malignant prostate tissues have markedly reduced zinc (Zn(2+)) contents in comparison to non-malignant tissues. In this study, we restored a high intracellular Zn(2+) level to LNCaP prostate cancer cells by culturing the cells in a growth medium supplemented with a supraphysiological concentration of Zn(2+) (10 microg/ml) over 5 weeks. The intracellular Zn(2+) level increased in the Zn(2+)-treated cells, and there was a marked increase in the presence of zincosomes, a Zn(2+)-specific intracellular organelle. The proliferation rate of the Zn(2+)-treated cells was markedly reduced. There was also a significant increase (36.6% +/- 6.4%) in the total tyrosine phosphorylated proteins. Vaccinia H1-related (VHR) phosphatase, zeta chain-associated protein-70 (ZAP-70) kinase and phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK 1 and 2) were also present in higher abundance. Treatment with TPEN, which chelates Zn(2+), reduced the abundance of VHR phosphatase and ZAP-70 kinase, but increased the abundance of p-ERK 1. However, the TPEN treatment restored the Zn(2+)-treated LNCaP cell proliferation to a rate comparable to that of the non Zn(2+)-treated cells. These results highlight the importance of a high intracellular Zn(2+) content and the VHR/ZAP-70-associated pathways in the modulation of LNCaP prostate cancer cell growth.
Matched MeSH terms: Protein Tyrosine Phosphatases/metabolism
The interconnected Ras/ERK and PI3K/AKT pathways play a central role in colorectal tumorigenesis, and they are targets for elucidating mechanisms involved in attempts to induce colon cancer cell death. Both ginger (Zingiber officinale) and honey have been shown to exhibit anti-tumor and anti-inflammation properties against many types of cancer, including colorectal cancer. However, there are currently no reports showing the combined effect of these two dietary compounds in cancer growth inhibition. The aim of this study was to evaluate the synergistic effect of crude ginger extract and Gelam honey in combination as potential cancer chemopreventive agents against the colorectal cancer cell line HT29.
Matched MeSH terms: Protein Tyrosine Phosphatases/genetics