-
1.
Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3.
Piao, L, Chen, Z, Li, Q, Liu, R, Song, W, Kong, R, Chang, S
International journal of molecular sciences. 2019;(1)
Abstract
Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95⁻associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the βN extension presents high flexibility in all systems, especially for M5P. The high flexibility of βN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with βN1' remain. In M5P system, although the interactions with βN1' are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the βN1' extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.
-
2.
Novel GLI3 Mutations in Chinese Patients with Non-syndromic Post-axial Polydactyly.
Chen, X, Yuan, L, Xu, H, Hu, P, Yang, Y, Guo, Y, Guo, Z, Deng, H
Current molecular medicine. 2019;(3):228-235
Abstract
BACKGROUND Polydactyly, characterized by supernumerary digits in the upper or lower extremities, is the most common congenital digital abnormalities. It derives from the defective patterning of anteroposterior axis of the developing limb, with various etiology and clinical heterogeneity. The patients with post-axial polydactyly type A (PAPA) have the typical symptom of a well-formed supernumerary digit outside the fifth digit. OBJECTIVE The aim of present study was to identify the causative mutations of two unrelated Han Chinese patients with non-syndromic PAPA. METHODS Two unrelated Han Chinese patients and 100 ethnicity-matched, unrelated normal controls were recruited for this study. BGISEQ-500 exome sequencing was performed in the two patients, followed by validation in the patients and 100 controls by using Sanger sequencing. RESULTS Two mutations in the GLI family zinc finger 3 gene (GLI3), including a frameshift mutation c.3437_3453delTCGAGCAGCCCTGCCCC (p.L1146RfsX95) and a nonsense mutation c.3997C>T (p.Q1333X), were identified in two patients but were absent in the 100 healthy controls. CONCLUSION The two GLI3 mutations, p.L1146RfsX95 and p.Q1333X, may account for non-syndromic PAPA in the two patients, respectively. The findings of this study may expand the mutational spectrum of GLI3-PAPA and provide novel insights into the genetic basis of polydactyly.
-
3.
Effects of upper-body resistance exercise training on serum nesfatin-1 level, insulin resistance, and body composition in obese paraplegic men.
Mogharnasi, M, TaheriChadorneshin, H, Papoli-Baravati, SA, Teymuri, A
Disability and health journal. 2019;(1):29-34
Abstract
BACKGROUND As a recently discovered adipokine, nesfatin-1 is conducive to insulin sensitivity, lipid profile, energy balance, and probably obesity. OBJECTIVE The aim of the present study was to investigate the effect of upper-body resistance exercise training (RET) on nesfatin-1 levels, insulin resistance, lipid profile, and body composition in obese paraplegic men. METHODS Twenty obese paraplegic men were randomly assigned into control and upper-body RET groups. Upper-body RET was performed for 8 weeks, 3 sessions per week at an intensity corresponding to 60-80% maximum amount of force that can be generated in one maximal contraction in 5 stations (bench press, seated rows, sitting lat pulldown, arm extension, and arm curls). Body fat percentage was determined according to 4-sites skinfold protocol of Durnin and Womersley and Siri equation. Obesity for spinal cord injury patients in the current study was set at BMI >22 kg/m2. Data were statistically analyzed by paired and independent t-test (P < 0.05). RESULTS We found significant improvements in serum levels of nesfatin-1 (21.13%), insulin sensitivity (8.95%), and high-density lipoprotein (10.87%). Other lipid profile markers, i.e. low-density lipoprotein (4.32%), cholesterol (8.20%), and triglyceride (15.10%) reduced significantly after upper-body RET. Moreover, upper-body RET led to a significant reduction in body mass index (2.36%), body fat percentage (2.79%), and waist-to-hip ratio (2.40%). CONCLUSION Upper-body RET improved insulin sensitivity, lipid profile, and body composition in paraplegic men. Serum nefastin-1 may be a potential marker of success in weight management in this population.
-
4.
Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.
Cleaver, R, Berg, J, Craft, E, Foster, A, Gibbons, RJ, Hobson, E, Lachlan, K, Naik, S, Sampson, JR, Sharif, S, et al
American journal of medical genetics. Part A. 2019;(3):344-349
Abstract
Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.
-
5.
Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor.
Kirberger, SE, Ycas, PD, Johnson, JA, Chen, C, Ciccone, MF, Woo, RWL, Urick, AK, Zahid, H, Shi, K, Aihara, H, et al
Organic & biomolecular chemistry. 2019;(7):2020-2027
-
-
Free full text
-
Abstract
Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.
-
6.
Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.
Haydar, S, Grigorescu, F, Vintilă, M, Cogne, Y, Lautier, C, Tutuncu, Y, Brun, JF, Robine, JM, Pugeat, M, Normand, C, et al
PloS one. 2019;(3):e0214122
Abstract
Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.
-
7.
Autistic symptoms in Greig cephalopolysyndactyly syndrome: a family case report.
Siracusano, M, Riccioni, A, Baratta, A, Baldi, M, Curatolo, P, Mazzone, L
Journal of medical case reports. 2019;(1):100
Abstract
BACKGROUND Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. CASE PRESENTATION We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. CONCLUSIONS We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.
-
8.
Variation in the repulsive guidance molecule family in human populations.
Rotwein, P
Physiological reports. 2019;(3):e13959
Abstract
Repulsive guidance molecules, RGMA, RGMB, and RGMC, are related proteins discovered independently through different experimental paradigms. They are encoded by single copy genes in mammalian and other vertebrate genomes, and are ~50% identical in amino acid sequence. The importance of RGM actions in human physiology has not been realized, as most research has focused on non-human models, although mutations in RGMC are the cause of the severe iron storage disorder, juvenile hemochromatosis. Here I show that repositories of human genomic and population genetic data can be used as starting points for discovery and for developing new testable hypotheses about each of these paralogs in human biology and disease susceptibility. Information was extracted, aggregated, and analyzed from the Ensembl and UCSC Genome Browsers, the Exome Aggregation Consortium, the Genotype-Tissue Expression project portal, the cBio portal for Cancer Genomics, and the National Cancer Institute Genomic Data Commons data site. Results identify extensive variation in gene expression patterns, substantial alternative RNA splicing, and possible missense alterations and other modifications in the coding regions of each of the three genes, with many putative mutations being detected in individuals with different types of cancers. Moreover, selected amino acid substitutions are highly prevalent in the world population, with minor allele frequencies of up to 37% for RGMA and up to 8% for RGMB. These results indicate that protein sequence variation is common in the human RGM family, and raises the possibility that individual variants will have a significant population impact on human physiology and/or disease predisposition.
-
9.
[Serum nesfatin-1 as a marker of systemic inflammation in rheumatoid arthritis.].
Kvlividze, TZ, Zavodovsky, BV, Akhverdyan, YR, Polyakova, YV, Sivordova, LE, Yakovlev, AT, Zborovskaya, IA
Klinicheskaia laboratornaia diagnostika. 2019;(1):53-56
Abstract
The purpose of this study was to determine the level of nesfatin-1 (NF-1) in the blood serum of healthy volunteers and patients with rheumatoid arthritis (RA) to establish the threshold for normal values of this parameter and to reveal the relationship between the level of NF-1 and clinical manifestations of RA. We examined 170 people, of which 110 patients with RA and 60 donors who made up the comparison group. The mean level of serum nesfatin-1 in healthy subjects was 31.61 ± 3.17 ng/ml (M ± σ). The level of normal values of nesfatin-1 in healthy individuals, defined as M ± 2σ, was from 25.27 to 37.95 ng/ml. These studies showed the relationship between the concentration of NF-1 and the severity of clinical manifestations of RA. We found that a higher serum level of NF-1 was characteristic of patients with a more severe clinical course of the disease. The data obtained indicate that high level of NF-1 positively correlates with higher concentrations of C-reactive protein and ESR. This data indirectly proves the proinflammatory effect of NF-1 and confirms the hypothesis about the primary role of systemic inflammation in the pathogenesis of RA.
-
10.
The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury: A prospective study.
Lyu, M, Zhou, J, Chen, H, Bai, H, Song, J, Liu, T, Cheng, Y, Ying, B
Medicine. 2019;(44):e17821
-
-
Free full text
-
Abstract
Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (PBonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686-6.139, PBonferroni correction = .003) or dominant model (PBonferroni correction = .003), as well as rs117806152 (Additive model: PBonferroni correction = .05; dominant model: PBonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (PBonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (PBonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487-6.896, PBonferroni correction = .02) and dominant model (PBonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI.