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Bi-allelic variants of FILIP1 cause congenital myopathy, dysmorphism and neurological defects

Roos A, van der Ven PFM, Alrohaif H, Kölbel H, Heil L, Della Marina A, et al.

Brain, 2023 Oct 03;146(10):4200-4216.
PMID: 37163662 DOI: 10.1093/brain/awad152

Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext ATG16L1 rs2241880/T300A increases susceptibility to perianal Crohn's disease: An updated meta-analysis on inflammatory bowel disease risk and clinical outcomes

Simovic I, Hilmi I, Ng RT, Chew KS, Wong SY, Lee WS, et al.

United European Gastroenterol J, 2024 Feb;12(1):103-121.
PMID: 37837511 DOI: 10.1002/ueg2.12477

BACKGROUND: ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis.
OBJECTIVES: To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features.
METHODS: Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP ) and 95% CI were calculated under the random effects model.
RESULTS: Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP : 1.21, 95% CI: 1.07-1.38, p-value: 0.003).
CONCLUSIONS: ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.

Matched MeSH terms: Carrier Proteins/genetics
Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers?

Singh S, Ganesh S

J Hum Genet, 2012 May;57(5):283-5.
PMID: 22456482 DOI: 10.1038/jhg.2012.29

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: Carrier Proteins/genetics*
Fulltext miR-524-5p of the primate-specific C19MC miRNA cluster targets TP53IPN1- and EMT-associated genes to regulate cellular reprogramming

Nguyen PNN, Choo KB, Huang CJ, Sugii S, Cheong SK, Kamarul T

Stem Cell Res Ther, 2017 09 29;8(1):214.
PMID: 28962647 DOI: 10.1186/s13287-017-0666-3

BACKGROUND: Introduction of the transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) is able to 'reprogram' somatic cells to become induced pluripotent stem cells (iPSCs). Several microRNAs (miRNAs) are known to enhance reprogramming efficiency when co-expressed with the OSKM factors. The primate-specific chromosome 19 miRNA cluster (C19MC) is essential in primate reproduction, development, and differentiation. miR-524-5p, a C19MC member, is highly homologous to the reprogramming miR-520d-5p; we also reported that miR-524-5p was expressed in iPSCs but not mesenchymal stem cells (MSCs). This study aimed to elucidate possible contributions of miR-524-5p to the reprogramming process.
METHODS: A miR-524-5p precursor was introduced into human fibroblast HFF-1 in the presence of OSKM, and the relative number of embryonic stem cell (ESC)-like colonies that stained positively with alkaline phosphatase (AP) and Nanog were quantified to determine reprogramming efficiency. A miR-524-5p mimic was transfected to MSCs to investigate the effects of miR-524-5p on TP53INP1, ZEB2, and SMAD4 expression by real-time polymerase chain reaction (PCR) and Western blot. Direct gene targeting was confirmed by luciferase activity. A phylogenetic tree of TP53INP1 was constructed by the Clustal method. Contribution of miR-524-5p to cell proliferation and apoptosis was examined by cell counts, BrdU, MTT, and cell death assays, and pluripotency gene expression by real-time PCR.
RESULTS: Co-expressing the miR-524 precursor with OSKM resulted in a two-fold significant increase in the number of AP- and Nanog-positive ESC-like colonies, indicating a role for miR-524-5p in reprogramming. The putative target, TP53INP1, showed an inverse expression relationship with miR-524-5p; direct TP53INP1 targeting was confirmed in luciferase assays. miR-524-5p-induced TP53INP1 downregulation enhanced cell proliferation, suppressed apoptosis, and upregulated the expression of pluripotency genes, all of which are critical early events of the reprogramming process. Interestingly, the TP53INP1 gene may have co-evolved late with the primate-specific miR-524-5p. miR-524-5p also promoted mesenchymal-to-epithelial transition (MET), a required initial event of reprogramming, by directly targeting the epithelial-to-mesenchymal transition (EMT)-related genes, ZEB2 and SMAD4.
CONCLUSIONS: Via targeting TP53INP1, ZEB2, and SMAD4, miR-524-5p contributes to the early stage of inducing pluripotency by promoting cell proliferation, inhibiting apoptosis, upregulating expression of pluripotency genes, and enhancing MET. Other C19MC miRNAs may have similar reprogramming functions.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext Normocyte-binding protein required for human erythrocyte invasion by the zoonotic malaria parasite Plasmodium knowlesi

Moon RW, Sharaf H, Hastings CH, Ho YS, Nair MB, Rchiad Z, et al.

Proc Natl Acad Sci U S A, 2016 Jun 28;113(26):7231-6.
PMID: 27303038 DOI: 10.1073/pnas.1522469113

The dominant cause of malaria in Malaysia is now Plasmodium knowlesi, a zoonotic parasite of cynomolgus macaque monkeys found throughout South East Asia. Comparative genomic analysis of parasites adapted to in vitro growth in either cynomolgus or human RBCs identified a genomic deletion that includes the gene encoding normocyte-binding protein Xa (NBPXa) in parasites growing in cynomolgus RBCs but not in human RBCs. Experimental deletion of the NBPXa gene in parasites adapted to growth in human RBCs (which retain the ability to grow in cynomolgus RBCs) restricted them to cynomolgus RBCs, demonstrating that this gene is selectively required for parasite multiplication and growth in human RBCs. NBPXa-null parasites could bind to human RBCs, but invasion of these cells was severely impaired. Therefore, NBPXa is identified as a key mediator of P. knowlesi human infection and may be a target for vaccine development against this emerging pathogen.

Matched MeSH terms: Carrier Proteins/genetics*
SPTAN1 encephalopathy: distinct phenotypes and genotypes

Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, et al.

J Hum Genet, 2015 Apr;60(4):167-73.
PMID: 25631096 DOI: 10.1038/jhg.2015.5

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

Matched MeSH terms: Carrier Proteins/genetics*
Interaction between a novel intronic IVS3+172 variant and N29I mutation in PRSS1 gene is associated with pancreatitis in a Malaysian Chinese family

Chua KH, Puah SM, Chew CH, Wong CH, Goh KL

Pancreatology, 2011;11(4):441-4.
PMID: 21952138 DOI: 10.1159/000330943

Hereditary pancreatitis (HP) is a very rare form of early-onset chronic pancreatitis, which usually begins in childhood with a variable spectrum of severity of disease. HP is commonly caused by variants/mutations in the PRSS1 gene as reported in many studies. Therefore, in this study, we aimed to investigate the possible association of PRSS1 gene variants/mutations in a Malaysian Chinese family with HP.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext Cloning and serotonergic regulation of RING finger protein38 (rnf38) in the brain of medaka (Oryzias latipes)

Moriya S, Khel NB, Parhar IS

Neuroscience, 2015 May 21;294:109-15.
PMID: 25772790 DOI: 10.1016/j.neuroscience.2015.03.012

Serotonin (5-HT) is a key regulator of mood and sexual behaviors. 5-HT reuptake inhibitors have been used as antidepressants. Really interesting new gene (RING) finger proteins have been associated with 5-HT regulation but their role remains largely unknown. Some RING finger proteins are involved in the serotonergic system, therefore, we speculate that the gene expression of RING finger protein38 (rnf38) is regulated by the serotonergic system. In the present study, we aimed to identify the full length sequence of medaka (Oryzias latipes) rnf38 mRNA and investigate its association with the serotonergic system using an antidepressant, citalopram (CIT). We identified the full length rnf38 cDNA, which consisted of 2726 nucleotides spanning 12 exons and the deduced protein sequence consisting of 518 amino acid residues including a RING finger domain, a KIT motif and a coiled-coil domain. Medaka exposed to 10(-7)M of CIT showed anxiety-like behavior. The expressions of 5-HT-related genes, pet1, solute carrier family 6, member 4A (slc6a4) and tryptophan hydroxylase (tph2) were significantly low (P<0.05) in the hindbrain. On the other hand, rnf38 gene was significantly high (P<0.05) in the telencephalon and the hypothalamus. This shows that 5-HT synthesis and transport in the hindbrain is suppressed by CIT, which induces rnf38 gene expression in the forebrain where 5-HT neurons project. Thus, the expression of rnf38 is negatively regulated by the serotonergic system.

Matched MeSH terms: Carrier Proteins/genetics
Existence of two emm-like "mrp" and "emm" genes in the mga regulon of the Streptococcus pyogenes strain ST4547

Eshaghi M, Ali AM, Jamal F, Yusoff K

J. Biochem. Mol. Biol. Biophys., 2002 Feb;6(1):23-8.
PMID: 12186779

Streptococcus pyogenes ST4547 is an opacity factor negative strain, which has been recently reported as a new emm type from Malaysia. Nucleotide sequencing of the mga regulon of this strain showed the existence of two emm-like genes. The emm gene located upstream of the scpA gene comprises 1305 nucleotides encoding the putative precursor M protein of 435 amino acids in length with an M(r) of 49 kDa. or a predicted mature protein of 394 amino acids with an M(r) of 44.8 kDa. Another gene mrpST4547 was located upstream of the emm gene and downstream of the mga gene. The sequence of this mrp gene comprises 1167 nucleotides encoding a predicted protein of 388 amino acids in length with an M(r) of 42.2 kDa. or a predicted mature protein of 347 amino acids with an M(r) of 37.9 kDa. The mga regulon of strain ST4547 has a mosaic structure comprising segments, which originated from different OF positive and OF negative strains. The sequences flanking the hyper-variable and C repeats of the emmST4547 gene showed high similarity to corresponding regions in the mga regulon of OF positive strains notably M15, M4, M22 and M50. In contrast, the sequence within the hyper-variable and C repeat regions of the emmST4547 gene revealed high similarity to equivalent regions in the OF negative strains. These data indicates that horizontal transfer of emm-like gene could have occurred between OF positive and OF negative strains resulting in architectural divergence in the mga regulon.

Matched MeSH terms: Carrier Proteins/genetics*
Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study

Song JH, Lee NY, Ichiyama S, Yoshida R, Hirakata Y, Fu W, et al.

Clin Infect Dis, 1999 Jun;28(6):1206-11.
PMID: 10451154

Antimicrobial susceptibility of 996 isolates of Streptococcus pneumoniae from clinical specimens was investigated in 11 Asian countries from September 1996 to June 1997. Korea had the greatest frequency of nonsusceptible strains to penicillin with 79.7%, followed by Japan (65.3%), Vietnam (60.8%), Thailand (57.9%), Sri Lanka (41.2%), Taiwan (38.7%), Singapore (23.1%), Indonesia (21.0%), China (9.8%), Malaysia (9.0%), and India (3.8%). Serotypes 23F and 19F were the most common. Pulsed-field gel electrophoresis (PFGE) of 154 isolates from Asian countries showed several major PFGE patterns. The serotype 23F Spanish clone shared the same PFGE pattern with strains from Korea, Japan, Singapore, Taiwan, Thailand, and Malaysia. Fingerprinting analysis of pbp1a, pbp2x, and pbp2b genes of 12 strains from six countries also showed identical fingerprints of penicillin-binding protein genes in most strains. These data suggest the possible introduction and spread of international epidemic clones into Asian countries and the increasing problems of pneumococcal drug resistance in Asian countries for the first time.

Matched MeSH terms: Carrier Proteins/genetics
Removal of poly-histidine fusion tags from recombinant proteins purified by expanded bed adsorption

Abdullah N, Chase HA

Biotechnol Bioeng, 2005 Nov 20;92(4):501-13.
PMID: 16080185

Enzymatic methods have been used to cleave the C- or N-terminus polyhistidine tags from histidine tagged proteins following expanded bed purification using immobilized metal affinity chromatography (IMAC). This study assesses the use of Factor Xa and a genetically engineered exopeptidase dipeptidyl aminopeptidase-1 (DAPase-1) for the removal of C-terminus and N-terminus polyhistidine tags, respectively. Model proteins consisting of maltose binding protein (MBP) having a C- or N-terminal polyhistidine tag were used. Digestion of the hexahistidine tag of MBP-His(6) by Factor Xa and HT15-MBP by DAPase-1 was successful. The time taken to complete the conversion of MBP-His(6) to MBP was 16 h, as judged by SDS-PAGE and Western blots against anti-His antibody. When the detagged protein was purified using subtractive IMAC, the yield was moderate at 71% although the overall recovery was high at 95%. Likewise, a yield of 79% and a recovery of 97% was obtained when digestion was performed with using "on-column" tag digestion. On-column tag digestion involves cleavage of histidine tag from polyhistidine tagged proteins that are still bound to the IMAC column. Digestion of an N-terminal polyhistidine tag from HT15-MBP (1 mg/mL) by the DAPase-I system was superior to the results obtained with Factor Xa with a higher yield and recovery of 99% and 95%, respectively. The digestion by DAPase-I system was faster and was complete at 5 h as opposed to 16 h for Factor Xa. The detagged MBP proteins were isolated from the digestion mixtures using a simple subtractive IMAC column procedure with the detagged protein appearing in the flowthrough and washing fractions while residual dipeptides and DAPase-I (which was engineered to exhibit a poly-His tail) were adsorbed to the column. FPLC analysis using a MonoS cation exchanger was performed to understand and monitor the progress and time course of DAPase-I digestion of HT15-MBP to MBP. Optimization of process variables such as temperature, protein concentration, and enzyme activity was developed for the DAPase-I digesting system on HT15-MBP to MBP. In short, this study proved that the use of either Factor Xa or DAPase-I for the digestion of polyhistidine tags is simple and efficient and can be carried out under mild reaction conditions.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext New emm (M protein gene) sequences of group A streptococci isolated from Malaysian patients

Jamal F, Pit S, Facklam R, Beall B

Emerg Infect Dis, 1999 Jan-Feb;5(1):182-3.
PMID: 10081694
Matched MeSH terms: Carrier Proteins/genetics*
Fulltext Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, et al.

Nat Genet, 2012 Oct;44(10):1142-1146.
PMID: 22922875 DOI: 10.1038/ng.2390

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Matched MeSH terms: Carrier Proteins/genetics*
Adenosine protects Sprague Dawley rats from high-fat diet and repeated acute restraint stress-induced intestinal inflammation and altered expression of nutrient transporters

Lee CY

J Anim Physiol Anim Nutr (Berl), 2015 Apr;99(2):317-25.
PMID: 25196093 DOI: 10.1111/jpn.12247

This study investigated the effect of repeated acute restraint stress and high-fat diet (HFD) on intestinal expression of nutrient transporters, concomitant to intestinal inflammation. The ability of adenosine to reverse any change was examined. Six-week-old male Sprague Dawley rats were divided into eight groups: control or non-stressed (C), rats exposed to restraint stress for 6 h per day for 14 days (S), control rats fed with HFD (CHF) and restraint-stressed rats fed with HFD (SHF); four additional groups received the same treatments and were also given 50 mg/l adenosine dissolved in drinking water. Fasting blood glucose, plasma insulin, adiponectin and corticosterone were measured. Intestinal expression of SLC5A1, SLC2A2, NPC1L1 and TNF-α was analysed. Histological evaluation was conducted to observe for morphological and anatomical changes in the intestinal tissues. Results showed that HFD feeding increased glucose and insulin levels, and repeated acute restraint stress raised the corticosterone level by 22%. Exposure to both stress and HFD caused a further increase in corticosterone to 41%, while decreasing plasma adiponectin level. Restraint stress altered intestinal expression of SLC5A1, SLC2A2 and NPC1L1. These changes were enhanced in SHF rats. Adenosine was found to alleviate HFD-induced increase in glucose and insulin levels, suppress elevation of corticosterone in S rats and improve the altered nutrient transporters expression profiles. It also prevented upregulation of TNF-α in the intestine of SHF rats. In summary, a combination of stress and HFD exaggerated stress- and HFD-induced pathophysiological changes in the intestine, and biochemical parameters related to obesity. Adenosine attenuated the elevation of corticosterone and altered expression of SLC5A1, NPC1L1 and TNF-α.

Matched MeSH terms: Carrier Proteins/genetics
Immunogenicity of a recombinant Mycobacterium bovis bacille Calmette-Guèrin expressing malarial and tuberculosis epitopes

Rapeah S, Norazmi MN

Vaccine, 2006 Apr 24;24(17):3646-53.
PMID: 16494975 DOI: 10.1016/j.vaccine.2006.01.053

Recombinant Mycobacterium bovis bacille Calmette-Guèrin (rBCG) expressing the malarial epitopes F2R(II)EBA and (NANP)3 as well as two T cell epitopes of the M. tuberculosis ESAT-6 antigen, generated in favour of mycobacterium codon usage elicited specific immune response against these epitopes. Immunised Balb/c mice demonstrated an increase in almost all of the IgG subclasses against both malarial epitopes and enhanced splenocyte proliferative response against the malarial epitopes as well as selected peptides of ESAT-6. Furthermore, flow cytometric analyses showed elevated numbers of CD4+ lymphocytes expressing IFN-gamma and IL-2 against the ESAT-6 peptides, suggesting a specific Th1-mediated response. This study demonstrated that expressing malarial and TB epitopes in a single rBCG construct induced appropriate humoral and cellular immune response against immunogenic epitopes from both organisms.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext Does Short-Term Dietary Omega-3 Fatty Acid Supplementation Influence Brain Hippocampus Gene Expression of Zinc Transporter-3?

Sopian NF, Ajat M, Shafie NI, Noor MH, Ebrahimi M, Rajion MA, et al.

Int J Mol Sci, 2015;16(7):15800-10.
PMID: 26184176 DOI: 10.3390/ijms160715800

Dietary omega-3 fatty acids have been recognized to improve brain cognitive function. Deficiency leads to dysfunctional zinc metabolism associated with learning and memory impairment. The objective of this study is to explore the effect of short-term dietary omega-3 fatty acids on hippocampus gene expression at the molecular level in relation to spatial recognition memory in mice. A total of 24 male BALB/c mice were randomly divided into four groups and fed a standard pellet as a control group (CTL, n = 6), standard pellet added with 10% (w/w) fish oil (FO, n = 6), 10% (w/w) soybean oil (SO, n = 6) and 10% (w/w) butter (BT, n = 6). After 3 weeks on the treatment diets, spatial-recognition memory was tested on a Y-maze. The hippocampus gene expression was determined using a real-time PCR. The results showed that 3 weeks of dietary omega-3 fatty acid supplementation improved cognitive performance along with the up-regulation of α-synuclein, calmodulin and transthyretin genes expression. In addition, dietary omega-3 fatty acid deficiency increased the level of ZnT3 gene and subsequently reduced cognitive performance in mice. These results indicate that the increased the ZnT3 levels caused by the deficiency of omega-3 fatty acids produced an abnormal zinc metabolism that in turn impaired the brain cognitive performance in mice.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext Differential Analysis of the Secretome of WRL68 Cells Infected with the Chikungunya Virus

Thio CL, Yusof R, Ashrafzadeh A, Bahari S, Abdul-Rahman PS, Karsani SA

PLoS One, 2015;10(6):e0129033.
PMID: 26083627 DOI: 10.1371/journal.pone.0129033

The Chikungunya virus (CHIKV) is an arthropod borne virus. In the last 50 years, it has been the cause of numerous outbreaks in tropical and temperate regions, worldwide. There is limited understanding regarding the underlying molecular mechanisms involved in CHIKV replication and how the virus interacts with its host. In the present study, comparative proteomics was used to identify secreted host proteins that changed in abundance in response to early CHIKV infection. Two-dimensional gel electrophoresis was used to analyse and compare the secretome profiles of WRL-68 cells infected with CHIKV against mock control WRL-68 cells. The analysis identified 25 regulated proteins in CHIKV infected cells. STRING network analysis was then used to predict biological processes that may be affected by these proteins. The processes predicted to be affected include signal transduction, cellular component and extracellular matrix (ECM) organization, regulation of cytokine stimulus and immune response. These results provide an initial view of CHIKV may affect the secretome of infected cells during early infection. The results presented here will compliment earlier results from the study of late host response. However, functional characterization will be necessary to further enhance our understanding of the roles played by these proteins in the early stages of CHIKV infection in humans.

Matched MeSH terms: Carrier Proteins/genetics
Fulltext Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Chornokur G, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Amankwah EK, et al.

PLoS One, 2015;10(6):e0128106.
PMID: 26091520 DOI: 10.1371/journal.pone.0128106

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.
METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.
RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).
CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Matched MeSH terms: Carrier Proteins/genetics*
Penicillin susceptibility and molecular characteristics of clinical isolates of Streptococcus pneumoniae at the University of Malaya Medical Center, Kuala Lumpur, Malaysia

Desa MN, Lin TK, Yasin RM, Parasakthi N

Int J Infect Dis, 2003 Sep;7(3):190-7.
PMID: 14563222

To determine the prevalence of penicillin resistance and molecular characteristics of pneumococcal isolates at the University of Malaya Medical Center.

Matched MeSH terms: Carrier Proteins/genetics
Blood-based dynamic genomic signature for obsessive-compulsive disorder

Wang Y, Cheng C, Zhang Z, Wang J, Wang Y, Li X, et al.

Am J Med Genet B Neuropsychiatr Genet, 2018 12;177(8):709-716.
PMID: 30350918 DOI: 10.1002/ajmg.b.32675

No biologically based diagnostic criteria are in clinical use today for obsessive-compulsive disorder (OCD), schizophrenia, and major depressive disorder (MDD), which are defined with reference to Diagnostic and Statistical Manual clinical symptoms alone. However, these disorders cannot always be well distinguished on clinical grounds and may also be comorbid. A biological blood-based dynamic genomic signature that can differentiate among OCD, MDD, and schizophrenia would therefore be of great utility. This study enrolled 77 patients with OCD, 67 controls with no psychiatric illness, 39 patients with MDD, and 40 with schizophrenia. An OCD-specific gene signature was identified using blood gene expression analysis to construct a predictive model of OCD that can differentiate this disorder from healthy controls, MDD, and schizophrenia using a logistic regression algorithm. To verify that the genes selected were not derived as a result of chance, the algorithm was tested twice. First, the algorithm was used to predict the cohort with true disease/control status and second, the algorithm predicted the cohort with disease/control status randomly reassigned (null set). A six-gene panel (COPS7A, FKBP1A, FIBP, TP73-AS1, SDF4, and GOLGA8A) discriminated patients with OCD from healthy controls, MDD, and schizophrenia in the training set (with an area under the receiver-operating-characteristic curve of 0.938; accuracy, 86%; sensitivity, 88%; and specificity, 85%). Our findings indicate that a blood transcriptomic signature can distinguish OCD from healthy controls, MDD, and schizophrenia. This finding further confirms the feasibility of using dynamic blood-based genomic signatures in psychiatric disorders and may provide a useful tool for clinical staff engaged in OCD diagnosis and decision making.

Matched MeSH terms: Carrier Proteins/genetics

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