Publications by authors named "Mohammad Reza Abbaszadegan"

143 Publications

Elucidated tumorigenic role of MAML1 and TWIST1 in gastric cancer is associated with Helicobacter pylori infection.

Microb Pathog 2021 Nov 21:105304. Epub 2021 Nov 21.

Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Epithelial-mesenchymal transition (EMT) has a fundamental role in tumor initiation, progression, and metastasis. Helicobacter pylori (HP) induces EMT and thus causes gastric cancer (GC) by deregulating multiple signaling pathways involved in EMT. TWIST1 and MAML1 have been confirmed to be critical inducers of EMT via diverse signaling pathways such as Notch signaling. This study aimed to investigate for the first time possible associations between TWIST1/MAML1 mRNA expression levels, HP infection, and clinicopathological characteristics in GC patients.

Method: TWIST1 and MAML1 mRNA expression levels were evaluated in tumoral and adjacent normal tissues in 73 GC patients using the quantitative reverse transcription PCR (RT-qPCR) method. PCR technique was also applied to examine the infection with HP in GC samples.

Results: Upregulation of TWIST1 and MAML1 expression was observed in 35 (48%) and 34 (46.6%) of 73 tumor samples, respectively. Co-overexpression of these genes was found in 26 of 73 (35.6%) tumor samples; meanwhile, there was a significant positive correlation between MAML1 and TWIST1 mRNA expression levels (P < 0.001). MAML1 overexpression exhibited meaningful associations with advanced tumor stages (P = 0.006) and nodal metastases (P ˂ 0.001). 34 of 73 (46.6%) tumors tested positive for HP, and meanwhile, MAML1 expression was positively related with T (P = 0.05) and grade (P = 0.0001) in these HP-positive samples. Increased TWIST1 expression was correlated with patient sex (P = 0.035) and advanced tumor grade (P = 0.017) in HP-infected tumors. Furthermore, TWIST1 and MAML1 expression levels were inversely linked with histologic grade in HP-negative tumor samples (P = 0.021 and P = 0.048, respectively).

Conclusion: We propose TWIST1 and MAML1 as potential biomarkers of advanced-stage GC that determine the characteristics and aggressiveness of the disease. Based on accumulating evidence and our findings, they can be introduced as promising therapeutic targets to modify functional abnormalities in cells that promote GC progression. Moreover, HP may enhance GC growth and metastasis by disrupting TWIS1/MAML1 expression patterns and related pathways.
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http://dx.doi.org/10.1016/j.micpath.2021.105304DOI Listing
November 2021

Genetically engineered mouse models of esophageal cancer.

Exp Cell Res 2021 09 28;406(2):112757. Epub 2021 Jul 28.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Esophageal cancer is the most common cause of cancer-related death worldwide with a diverse geographical distribution, poor prognosis, and diagnosis in advanced stages of the disease. Identification of the mechanisms involved in esophageal cancer development is evaluative to improve outcomes for patients. Genetically engineered mouse models (GEMMs) of cancer provide the physiologic, molecular, and histologic features of the human tumors to determine the pathogenesis and treatments for cancer, hence exhibiting a source of tremendous potential for oncology research. The advancement of cancer modeling in mice has improved to the extent that researchers can observe and manipulate the disease process in a specific manner. Despite the significant differences between mice and humans, mice can be great models for human oncology researches due to similarities between them at the molecular and physiological levels. Due to most of the existing esophageal cancer GEMMs do not propose an ideal system for pathogenesis of the disease, genetic risks, and microenvironment exposure, so identification of challenges in GEM modeling and well-developed technologies are required to obtain the most value for patients. In this review, we describe the biology of human and mouse, followed by the exciting esophageal cancer mouse models with a discussion of applicability and challenges of these models for generating new GEMMs in future studies.
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http://dx.doi.org/10.1016/j.yexcr.2021.112757DOI Listing
September 2021

The Level of Mesenchymal-Epithelial Transition Autophosphorylation is Correlated with Esophageal Squamous Cell Carcinoma Migration.

Iran Biomed J 2021 07 1;25(4):243-54. Epub 2021 Jul 1.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The MET receptor is a critical member of cancer-associated receptor tyrosine kinases and plays an important role in different biological activities, including differentiation, migration, and cell proliferation.

Methods: In this study, novel MET inhibitors were introduced and applied on esophageal squamous carcinoma cell line KYSE-30, and the level of proliferation and migration, as well as the activated form of MET receptor protein were assessed in the examined cells. The human KYSE-30 cell line was cultured according to ATCC recommendations. The mRNA level of the MET gene was measured in the examined cell line using the quantitative RT-PCR assay. Cytotoxicity evaluation test was performed at different concentrations of heterocyclic anti-MET compounds (i.e. D1, D2, D5, D6, D7, and D8). Finally, the capability of these compounds in MET receptor inhibition was evaluated using the migration assay and Western blot. All experiments were performed in triplicate and repeated three times with similar results.

Results: Cell growth and proliferation were significantly inhibited (p ≤ 0.05) by all the above-mentioned compounds. Moreover, the majority of compounds significantly prevented the cell migration (p ≤ 0.05) and inhibited MET autophosphorylation. Interestingly, the level of phosphorylated MET was significantly correlated with KYSE-30 cell migration.

Conclusion: The obtained data introduced and confirmed the biological activities of the mentioned novel compounds in KYSE-30 cells and proposed that the therapeutic inhibition of MET with these compounds may be a powerful approach for inhibiting cancer cell migration and proliferation although some structural optimizations are needed to improve their inhibitory functions.
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http://dx.doi.org/10.52547/ibj.25.4.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8334392PMC
July 2021

Non-collagenous extracellular matrix protein dermatopontin may play a role as another component of transforming growth factor-β signaling pathway in colon carcinogenesis.

Iran J Basic Med Sci 2021 Apr;24(4):444-450

Medical Genetic Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Dermatopontin (DPT) is an extracellular matrix protein that plays roles in increasing the activity of transforming growth factor-β (TGF-β) and induction of cell quiescence. These roles suggest a tumor suppressor function for DPT. This study aimed to investigate changes in DPT gene expression in colorectal cancer providing a better understanding of its carcinogenesis.

Materials And Methods: We used Matched Tumor/Normal Expression Array and Cancer Profiling Arrays I containing 34 and 7 cases of colorectal cancer and their matched controls, respectively, to test DPT expression. In addition, 38 newly diagnosed cases of colorectal cancer were enrolled and their fresh colonic tumoral and normal specimens were obtained. DPT mRNA expression was analyzed using real-time PCR. In cases with DPT under expression, exonic regions of the DPT gene were sequenced using the Sanger method.

Results: In array samples, DPT expression was decreased in 82.9% (34/41), increased in 12.2% (5/41), and had no changes in 4.9% (2/41). DPT was decreased in 14 fresh samples (36.8%), while 12 cases (31.6%) showed overexpression and the others had no changes. DPT expression showed no significant difference among various tumor grades and stages. The frequencies of DPT overexpression were higher in tumors having lymph node involvement (47.7% vs 28%, =0.59). In 2 cases mutations were detected that may be responsible for decreased expression of DPT.

Conclusion: The similarities between changing patterns of DPT and TGF-β expression in colorectal cancer demonstrate that DPT may act as a pre-receptor component of the TGF-β signaling pathway in colon carcinogenesis.
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http://dx.doi.org/10.22038/IJBMS.2021.46422.10720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143710PMC
April 2021

Genotyping of , and in Iranian Infants with Congenital Hyperinsulinism.

Case Rep Endocrinol 2021 13;2021:8826174. Epub 2021 May 13.

Medical Genetic Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, , and genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in , and genes as causative genes for CHI in the Iranian population.

Methods: The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in , and genes were analyzed by the polymerase chain reaction and sequencing in our patients.

Results: Among 20 pediatric patients, 16 of them had variants in , and genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > ) mutation in the gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the gene and a missense variant (c.287-288delinsTG) in the gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present.

Conclusion: Most variants were located in the gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted.
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http://dx.doi.org/10.1155/2021/8826174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137283PMC
May 2021

Single nucleotide polymorphisms as the efficient prognostic markers in breast cancer.

Curr Cancer Drug Targets 2021 May 25. Epub 2021 May 25.

Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Breast cancer (BC) is known as the most common malignancy in women. Environmental and genetic factors are associated with BC progression. Genetic polymorphisms have been reported as important risk factors of BC prognosis and drug response. Main body: Therefore, in the present review, we have summarized all single nucleotide polymorphisms (SNPs) which have been significantly associated with drug response in BC patients around the world. We have also categorized the reported SNPs based on their related genes functions to clarify the molecular biology of drug responses in BC.

Conclusion: The majority of SNPs were reported in detoxifying enzymes, which introduced such genes as the main genetic risk factors during BC drug responses. This review paves the way for introducing a prognostic panel of SNPs for the BC patients in the world.
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http://dx.doi.org/10.2174/1568009621666210525151846DOI Listing
May 2021

MAEL as a diagnostic marker for the early detection of esophageal squamous cell carcinoma.

Diagn Pathol 2021 Apr 26;16(1):36. Epub 2021 Apr 26.

Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Esophageal cancer is one of the most common malignancies among Iranians and is categorized as adenocarcinoma and squamous cell carcinoma. Various environmental and genetic factors are involved in this malignancy. Despite the recent advances in therapeutic modalities there is still a noticeable mortality rate among such patients which can be related to the late diagnosis. Regarding high ratio of esophageal squamous cell carcinoma (ESCC) in Iran, therefore it is required to assess molecular biology of ESCC to introduce novel diagnostic markers. In present study we assessed the role of Maelstrom (MAEL) cancer testis gene in biology of ESCC among Iranian patients.

Methods: Forty-five freshly normal and tumor tissues were enrolled to evaluate the levels of MAEL mRNA expression using Real time polymerase chain reaction.

Results: MAEL under and over expressions were observed in 12 (26.7%) and 9 (20%) of patients, respectively. MAEL fold changes were ranged between -4.33 to -1.87 (mean SD: -2.90± 0.24) and 1.92 to 7.72 (mean SD: 3.97± 0.69) in under and over expressed cases, respectively. There was a significant association between stage and MAEL expression in which majority of MAEL over expressed tumors (8/9, 88.9%) were in stage I/II (p<0.001). There was also a significant correlation between MAEL expression and depth of invasion in which tumor with T1/2 had higher levels of MAEL expression compared with T3/4 tumors (p=0.017). Moreover, there were significant correlations between MAEL expression, tumor size (p=0.028), and grade (p=0.003) among male patients.

Conclusions: Our data showed that the MAEL was mainly involved in primary stages of tumor progression and it has a declining expression levels toward the advanced stages and higher depth of tumor invasions. Therefore, MAEL can be efficiently introduced as an early detection marker among Iranian ESCC patients.
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http://dx.doi.org/10.1186/s13000-021-01098-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077922PMC
April 2021

Correlation between the immune checkpoints and EMT genes proposes potential prognostic and therapeutic targets in ESCC.

J Mol Histol 2021 Jun 21;52(3):597-609. Epub 2021 Apr 21.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3, crucial immune checkpoint molecules in the tumor microenvironment, identify as key targets for cancer immunotherapy. There is a correlation between immune cells and epithelial-mesenchymal transition (EMT)-related genes expression in varies human cancers. In this study, we aimed to investigate the probable association between expression of immune checkpoints and EMT in esophageal squamous cell carcinoma (ESCC) with clinical treats for providing the new therapeutic targets and prognostic value for the disease. Quantitative real-time PCR was used to investigate the gene expression profile of immune checkpoints (PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3) and EMT (TWIST1 and MMP-13) genes based on the mRNA expression levels in 51 ESCC tissues. The upregulation of CTLA-4, PD-1, PD-L1, TIM-3, LAG-3, MMP-13, and TWIST1 were observed in 31.37%, 29.41%, 21.56%, 39.21%, 25.49%, 60.78%, and 56.86% of ESCC cases at the mRNA level, respectively. Dysregulation of immune checkpoints was related to lymph node involvement, stage of tumor progression, and depth of tumor invasion (P < 0.05). While overexpression of MMP-13 and TWIST1 was associated with lymph node involvement, stage of tumor progression, and grade of tumor differentiation (P < 0.05). The mRNA expression of immune checkpoint genes was significantly correlated to each other's (P = 0.000). Of importance, the data explored the significant association between the concomitant expression of immune checkpoints and EMT-related genes with each other in a variety of clinicopathological traits (P < 0.05). Consequently, immune checkpoints were positively correlated with EMT status in ESCC. The correlation between tumor immune microenvironment with the elevation of multiple immune checkpoints and EMT status may help to identify potential biomarkers for the simultaneous clinical use of multiple immune checkpoints blockade and other immunotherapies approaches for advanced ESCC patients.
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http://dx.doi.org/10.1007/s10735-021-09971-3DOI Listing
June 2021

Methylation as a critical epigenetic process during tumor progressions among Iranian population: an overview.

Genes Environ 2021 Apr 21;43(1):14. Epub 2021 Apr 21.

Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Cancer is one of the main health challenges and leading causes of deaths in the world. Various environmental and genetic risk factors are associated with tumorigenesis. Epigenetic deregulations are also important risk factors during tumor progression which are reversible transcriptional alterations without any genomic changes. Various mechanisms are involved in epigenetic regulations such as DNA methylation, chromatin modifications, and noncoding RNAs. Cancer incidence and mortality have a growing trend during last decades among Iranian population which are significantly related to the late diagnosis. Therefore, it is required to prepare efficient molecular diagnostic panels for the early detection of cancer in this population. Promoter hyper methylation is frequently observed as an inhibitory molecular mechanism in various genes associated with DNA repair, cell cycle regulation, and apoptosis during tumor progression. Since aberrant promoter methylations have critical roles in early stages of neoplastic transformations, in present review we have summarized all of the aberrant methylations which have been reported during tumor progression among Iranian cancer patients. Aberrant promoter methylations are targetable and prepare novel therapeutic options for the personalized medicine in cancer patients. This review paves the way to introduce a non-invasive methylation specific panel of diagnostic markers for the early detection of cancer among Iranians.
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http://dx.doi.org/10.1186/s41021-021-00187-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059047PMC
April 2021

Interaction between LINC-ROR and Stemness State in Gastric Cancer Cells with Helicobacter pylori Infection.

Iran Biomed J 2021 Mar 1;25(3):157-68. Epub 2021 Mar 1.

Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Large intergenic non-coding RNA regulator of reprogramming (LINC-ROR), as a cancer-related Long non-coding RNA, has vital roles in stem cell survival, pluripotency, differentiation, and self-renewal in human embryonic stem cell. However, cancer-related molecular mech¬anisms, its functional roles, and clinical value of LINC-ROR in gastric cancer (GC) remain unclear. In this study, we aimed to investigate probable interplay between LINC-ROR with SALL4 stemness regulator and their role with the development of the disease.

Methods: The mRNA expression profile of LINC-ROR and SALL4 was assessed in tumoral and adjacent non-cancerous tissues of GC patients, using quantitative real-time PCR.

Results: Significant LINC-ROR underexpression and SALL4 overexpression were observed in 55.81% and 75.58% (p < 0.0001) of samples, respectively. The expression of LINC-ROR and SALL4 were significantly correlated with each other (p = 0.044). There was an association between the underexpression of LINC-ROR and sex, stage of tumor progression, tumor type, and location of tumor (p < 0.05), and Helicobacter pylori infection with SALL4 expression (p = 0.036). There were also significant correlations between concomitant mRNA expression of SALL4 and LINC-ROR in tumors located at distal noncardiac, positive for H. pylori infection, tumors with invasion into the muscle layer of the stomach, and grade II tumor (p < 0.05).

Conclusion: The clinical results of the SALL4-LINC-ROR association propose a probable functional interaction between these markers in tumor maintenance and aggressiveness. Our study can help to understand one of the mechanisms involved in the progression of gastric cancer through the function of these regulators.
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http://dx.doi.org/10.29252/ibj.25.3.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183384PMC
March 2021

Role of miRNA gene variants in the susceptibility and pharmacogenetics of colorectal cancer.

Pharmacogenomics 2021 04 18;22(5):303-318. Epub 2021 Mar 18.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer (CRC) is one of the most significant challenges in the field of cancer pathology. miRNAs are among the genetic factors associated with the disease. Although many studies have reviewed the expression patterns of various miRNAs in CRC, few studies have focused on different variants of miRNA. In the present review, miRNA variants have been categorized into three subgroups, including miRNA variants that predict susceptibility to CRC, miRNA variants that predict the clinical parameters of CRC and finally, miRNA variants that predict the pharmacological aspects of CRC. Moreover, a comprehensive review of potentially functional miRNA-associated SNPs as well as their importance as candidate cancer biomarkers are discussed.
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http://dx.doi.org/10.2217/pgs-2020-0159DOI Listing
April 2021

A Systematic Review on the Genotoxic Effects of Selective Serotonin Reuptake Inhibitors.

Adv Exp Med Biol 2021 ;1286:115-124

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Depression is a mental disorder and a major public health concern affecting millions of people worldwide. It is a common disorder that has been associated with several medical comorbidities often linked with aging, such as dementia, type II diabetes, cardiovascular and cerebrovascular diseases, as well as metabolic syndrome. There are a variety of medications available for depression treatment. Selective serotonin reuptake inhibitors (SSRIs) are one of the antidepressant drug classes that are most widely used to treat depressive disorders and depressive symptoms in other diseases. Due to many contradictory findings on the adverse effects and toxicities of SSRIs (especially genotoxicities), we reviewed the genotoxic effects of these drugs. Based on the guidelines proposed in the PRISMA statement, we performed a systematic review by searching international electronic databases including PubMed, Scopus, Embase, and Web of Science to find the published documents on SSRIs and their genotoxic effects from January 1990 to November 2019. After the removal of 203 duplicate articles, 385 articles were screened and 167 articles met the inclusion criteria and qualified for evaluation of their full texts. After this, 26 articles were appropriate for final review. This revealed that the proportion of genotoxicities was highest for citalopram and fluoxetine, with a smaller proportion for sertraline. Limited documentations showed genotoxic and partial genotoxic effects for paroxetine and escitalopram, respectively. Although a number of studies have found genotoxic effects of SSRIs, there are also some factors including doses, duration of exposure, model of experiments, and the type of technique assay that may affect the results.
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http://dx.doi.org/10.1007/978-3-030-55035-6_8DOI Listing
March 2021

Crosstalk between MMP-13, CD44, and TWIST1 and its role in regulation of EMT in patients with esophageal squamous cell carcinoma.

Mol Cell Biochem 2021 Jun 19;476(6):2465-2478. Epub 2021 Feb 19.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Matrix metalloproteinases (MMPs) play key roles in epithelial-mesenchymal transition (EMT) for the development of cancer cell invasion and metastasis. MMP-13 is an extracellular matrix (ECM)-degrading enzyme that plays crucial roles in angiogenesis, cell cycle regulation, niche maintenance, and transforming squamous epithelial cells in various tissues. CD44, a transmembrane glycoprotein expressed on esophageal tumor cells, is required for EMT induction and invasion in esophageal squamous cell carcinoma (ESCC). The transcription factor TWIST1, as EMT and stemness marker, regulates MMPs expression and is identified as the downstream target of CD44. In this study, we aimed to investigate the probable interplay between the expression of key genes contributing to ESCC development, including MMP-13, TWIST1, and CD44 with clinical features for introducing novel diagnostic and therapeutic targets in the disease. The gene expression profiling of MMP-13, TWIST1, and CD44 was performed using quantitative real-time PCR in tumor tissues from 50 ESCC patients compared to corresponding margin non-tumoral tissues. Significant overexpression of MMP-13, CD44S, CD44V3, CD44V6, and TWIST1 were observed in 74%, 36%, 44%, 44%, and 52% of ESCC tumor samples, respectively. Overexpression of MMP-13 was associated with stage of tumor progression, metastasis, and tumor location (P < 0.05). There was a significant correlation between TWIST1 overexpression and grade (P < 0.05). Furthermore, overexpression of CD44 variants was associated with stage of tumor progression, grade, tumor invasion, and location (P < 0.05). The results indicated the significant correlation between concomitant expression of MMP-13/TWIST1, TWIST1/CD44, and CD44/MMP-13 with each other in a variety of clinicopathological traits, including depth of tumor invasion, tumor location, stage of tumor, and lymph node involvement in ESCC tissue samples (P < 0.05). Collectively, our results indicate that the TWIST1-CD44-MMP-13 axis is involved in tumor aggressiveness, proposing these genes as regulators of EMT, diagnostic markers, and therapeutic targets in ESCC.
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http://dx.doi.org/10.1007/s11010-021-04089-2DOI Listing
June 2021

Genetic and molecular biology of systemic lupus erythematosus among Iranian patients: an overview.

Auto Immun Highlights 2021 Jan 30;12(1). Epub 2021 Jan 30.

Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Systemic lupus erythematosus (SLE) is a clinicopathologically heterogeneous chronic autoimmune disorder affecting different organs and tissues. It has been reported that there is an increasing rate of SLE incidence among Iranian population. Moreover, the Iranian SLE patients have more severe clinical manifestations compared with other countries. Therefore, it is required to introduce novel methods for the early detection of SLE in this population. Various environmental and genetic factors are involved in SLE progression.

Main Body: In present review we have summarized all of the reported genes which have been associated with clinicopathological features of SLE among Iranian patients.

Conclusions: Apart from the reported cytokines and chemokines, it was interestingly observed that the apoptosis related genes and non-coding RNAs were the most reported genetic abnormalities associated with SLE progression among Iranians. This review clarifies the genetics and molecular biology of SLE progression among Iranian cases. Moreover, this review paves the way of introducing an efficient panel of genetic markers for the early detection and better management of SLE in this population.
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http://dx.doi.org/10.1186/s13317-020-00144-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847600PMC
January 2021

mutations identified in autism spectrum disorder using forward genetics.

Elife 2020 12 22;9. Epub 2020 Dec 22.

Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified as a candidate ASD gene. To validate our discovery, we generated a knockout mouse model () and confirmed that inactivating disrupts vocalization. In addition, mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.
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http://dx.doi.org/10.7554/eLife.56883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755391PMC
December 2020

Examining the Frequency of the (V617F) Mutation in Patients with Myeloproliferative Diseases in North Eastern Iran and the Effect of Treatment Intervention.

Rep Biochem Mol Biol 2020 Jul;9(2):188-192

Pardis Clinical and Genetics Laboratory, Mashhad, Iran.

Background: Janus kinase 2 () is a tyrosine kinase located in the cytoplasm that plays a critical role in the signal transduction of cytokines and growth hormones. The conversion of valine to phenylalanine at the polypeptide position 617 results in the (V617F) mutation, which often found in patients with myeloproliferative neoplasms (MPNs). As a result of this mutation, is constitutively activated leading to uncontrolled cell growth. The present study aimed to investigate the frequency and relationship of the (V617F) mutation in a population of patients with MPNs in Iran.

Methods: A total of 213 patients with myeloproliferative diseases (MPDs), were included in the study. Real-time PCR was used to detect the presence of the (V617F) mutation in the genomic DNA isolated from patient peripheral blood samples.

Results: Of the 213 patients with MPDs, approximately 60 (28%) patients were positive for the (V617F) mutation. Polycythemia Vera (PV, 42.11%) was the most common MPD, followed by Essential Thrombocythemia (ET, 29.82%), Primary Myelofibrosis (MF, 12.28%), and Chronic Myeloid Leukemia (CML, 10.5%). A significant relationship between all types of MPDs and the clinical course (p< 0.05) was observed. The relationship between age and gender among all types of MPD disease was not significant (p> 0.05).

Conclusion: Of the examined cohort in North Eastern Iran, 28% of the patients with MPNs were found to have the (V617F) mutation which determining the presence of the (V617F) mutation helps to decide the correct form of treatment.
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http://dx.doi.org/10.29252/rbmb.9.2.188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603260PMC
July 2020

SOX2/SALL4 stemness axis modulates Notch signaling genes to maintain self-renewal capacity of esophageal squamous cell carcinoma.

Mol Cell Biochem 2021 Feb 24;476(2):921-929. Epub 2020 Oct 24.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Stemness phenotype is considered as the centerpiece of cancer biology due to its potential in conventional chemo-radiotherapy resistance and tumor recurrence after clinical intervention. This feature in tumor mass belongs to activation of core regulatory stemness factors and different cell signaling pathways in cancer stem cells. We aimed in this study to elucidate contribution of Notch signaling pathway in stemness state of esophageal squamous cell carcinoma (ESCC) through their relevance with stem cell markers SOX2 and SALL4. 50 ESCC tumor and related margin normal tissues were considered and categorized based on SOX2/SALL4 expression pattern, and mRNA levels of Notch signaling genes including ligands, receptors, target genes, and transcriptional coactivator were analyzed in the selected groups using qRT-PCR. Concomitant overexpression of stem cell markers SOX2 and SALL4 in ESCCs upregulated the involved genes in Notch signaling pathway. Upregulation of Notch pathway genes associated with depth of tumor invasion and lymph node metastasis of ESCC. Based on biological function of SOX2 and SALL4 axis in stemness state potential, our results may suggest contribution of Notch signaling pathway in self-renewal capacity of ESCCs, as well as invasion and metastasis of the disease. To the best of our knowledge, this is the first report elucidating the crosstalk between SOX2/SALL4 stemness factors and Notch signaling pathway in cancer research.
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http://dx.doi.org/10.1007/s11010-020-03956-8DOI Listing
February 2021

Mechanisms of long non-coding RNA function in colorectal cancer tumorigenesis.

Asia Pac J Clin Oncol 2021 Feb 24;17(1):7-23. Epub 2020 Sep 24.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug-resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.
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http://dx.doi.org/10.1111/ajco.13452DOI Listing
February 2021

Integration analysis of long non-coding RNA (lncRNA) role in tumorigenesis of colon adenocarcinoma.

BMC Med Genomics 2020 07 29;13(1):108. Epub 2020 Jul 29.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Colon adenocarcinoma (COAD) is one of the most common gastrointestinal cancers globally. Molecular aberrations of tumor suppressors and/or oncogenes are the main contributors to tumorigenesis. However, the exact underlying mechanisms of COAD pathogenesis are clearly not known yet. In this regard, there is an urgent need to indicate promising potential diagnostic and prognostic biomarkers in COAD patients.

Methods: In the current study, level 3 RNA-Seq and miR-Seq data and corresponding clinical data of colon adenocarcinoma (COAD) were retrieved from the TCGA database. The "limma" package in R software was utilized to indicate the differentially expressed genes. For in silico functional analysis, GO and KEGG signaling pathways were conducted. PPI network was constructed based on the STRING online database by Cytoscape 3.7.2. A ceRNA network was also constructed by "GDCRNATools" package in R software. Kaplan-Meier survival analysis (log-rank test) and ROC curve analysis were used to indicate the diagnostic and prognostic values of the biomarkers.

Results: The differential expression data demonstrated that 2995 mRNAs, 205 lncRNAs, and 345 miRNAs were differentially expressed in COAD. The GO and KEGG pathway analysis indicated that the differentially expressed mRNAs were primarily enriched in canonical processes in cancer. The PPI network showed that the CDKN2A, CCND1, MYC, E2F, CDK4, BRCA2, CDC25B, and CDKN1A proteins were the critical hubs. In addition, the Kaplan-Meier analysis revealed that 215 mRNAs, 14 lncRNAs, and 39 miRNAs were associated with overall survival time in the patients. Also, the ceRNA network data demonstrated that three lncRNAs including MIR17HG, H19, SNHG1, KCNQ1OT1, MALAT1, GAS5, SNHG20, OR2A1-AS1, and MAGI2-AS3 genes were involved in the development of COAD.

Conclusions: Our data suggested several promising lncRNAs in the diagnosis and prognosis of patients with COAD.
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http://dx.doi.org/10.1186/s12920-020-00757-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392656PMC
July 2020

TWIST1 upregulates matrix metalloproteinase (MMP) genes family in esophageal squamous carcinoma cells.

Gene Expr Patterns 2020 09 22;37:119127. Epub 2020 Jul 22.

Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran. Electronic address:

Twist-related protein 1 (TWIST1), a highly conserved basic helix-loop-helix transcription factor, stimulates epithelial-mesenchymal transition (EMT) and plays a crucial role in the regulation of the extracellular matrix (ECM) and cell-cell adhesion. Our aim in this study was to evaluate the functional correlation between TWIST1 and MMP genes in human ESCC cell lines, KYSE-30 and YM-1. To generate recombinant retroviral particles, the Pruf-IRES-GFP-hTWIST1 was co-transfected into HEK293T along with pGP and pMD2. G as well as Pruf-IRES-GFP control plasmid. Stably transduced high-expressing GFP-hTWIST1 and GFP-control KYSE-30 cells were generated. The produced retroviral particles were transduced into the KYSE-30 and YM-1 ESCC cells. Ectopic expression of TWIST1 mRNA and expression of the MMP genes (MMP-2, MMP-3, MMP-7, MMP-9, and MMP-10) were examined by relative comparative real-time PCR. In silico analysis of the MMP markers and their promoter elements was explored. Moreover, the scratch wound assay was used to evaluate the migration of TWIST1-induced cells. TWIST1 level was up-regulated by nearly 5-fold and 7.4-fold in GFP-hTWIST1 KYSE-30 and YM-1 cells compared to GFP control cells, respectively. Interestingly, this enforced expression of TWIST1 subsequently caused significant overexpression of transcripts for selected MMP genes in GFP-hTWIST1 in comparison with GFP control cells in both ESCC cell lines. Also, the scratch assay indicated that TWIST1 expression effectively increased the migration of GFP-TWIST1 KYSE-30 cells against GFP KYSE-30 control cells in vitro. The present findings illuminate that TWIST1 may contribute broadly to ESCC development in concert with up-regulation of MMPs expression and further suggest the potential advantage of exerting TWIST1/MMPs signaling axis as a framework from which to expand our understanding about the mechanisms of ESCC tumorigenesis.
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http://dx.doi.org/10.1016/j.gep.2020.119127DOI Listing
September 2020

GSTs polymorphisms are associated with epigenetic silencing of CDKN2A gene in esophageal squamous cell carcinoma.

Environ Sci Pollut Res Int 2020 Sep 1;27(25):31269-31277. Epub 2020 Jun 1.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Esophageal cancer is the eighth most common cancer and the sixth most frequent cause of cancer mortality worldwide. Exposure to polycyclic aromatic hydrocarbons formed by incomplete combustion of organic matter is an important risk factor. Genetic polymorphisms in genes encoding PAH-metabolizing enzymes like glutathione S-transferases (GSTM1, GSTP1, GSTT1) which conjugate glutathione to PAHs for reduction of oxidative stress may affect an individual's response to PAH exposure. Genomic DNA from 50 esophageal squamous cell carcinoma patients extracted from peripheral blood. PCR-RFLP technique was employed to determine GSTM1, GSTT1, and GSTP1 polymorphisms. Aberrant promoter methylation of CDKN2A was applied by methylation-specific PCR technique. Concentration of urinary 1-hydroxypyrene was determined using a HPLC system. About 38.7% showed the null GSTM1 genotype (54% cases and 13% controls), 23.7% showed GSTT1 null genotype (30% cases and 13% controls), and 62.5% were GSTP1 A/A genotype (66% cases and 56% controls). Polymorphic variants of GSTM1 and GSTT1 were significantly associated with aberrant methylation of CDKN2A gene. The null state of GSTT1 was significantly associated with high concentrations of 1-OHP in urea (p < 0.01). There was significant association between methylated states of CDKN2A and high concentrations of 1-OHP in urine (p < 0.01). We identified significant association between polymorphism of GSTs genes and epigenetic silencing of tumor suppressor gene CDKN2A in esophageal squamous cell carcinoma.
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http://dx.doi.org/10.1007/s11356-020-09408-6DOI Listing
September 2020

Role of extra cellular proteins in gastric cancer progression and metastasis: an update.

Genes Environ 2020 15;42:18. Epub 2020 May 15.

2Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Gastric cancer (GC) is one of the most common cancers in the world with a high ratio of mortality. Regarding the late diagnosis, there is a high ratio of distant metastasis among GC cases. Despite the recent progresses in therapeutic modalities, there is not still an efficient therapeutic method to increase survival rate of metastatic GC cases.

Main Body: Apart from the various intracellular signaling pathways which are involved in tumor cell migration and metastasis, the local microenvironment is also a critical regulator of tumor cell migration. Indeed, the intracellular signaling pathways also exert their final metastatic roles through regulation of extra cellular matrix (ECM). Therefore, it is required to assess the role of extra cellular components in biology of GC.

Conclusion: In the present review, we summarize 48 of the significant ECM components including 17 ECM modifying enzymes, seven extracellular angiogenic factors, 13 cell adhesion and cytoskeletal organizers, seven matricellular proteins and growth factors, and four proteoglycans and extra cellular glycoproteins. This review paves the way of determination of a specific extra cellular diagnostic and prognostic panel marker for the GC patients.
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http://dx.doi.org/10.1186/s41021-020-00157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227337PMC
May 2020

Novel Deleterious Mutation in Steroid-5α-Reductase-2 in 46, XY Disorders of Sex Development: Case Report Study.

Fetal Pediatr Pathol 2020 May 25:1-8. Epub 2020 May 25.

Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Steroid-5α-reductase-2 (SRD5A2) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme deficiencies are frequent causes of 46, XY disorder of sex development (46, XY DSD), where an infant with 46, XY has a female phenotype. We assessed the hydroxy-steroid-17β-dehydrogenase-3 (HSD17B3)and SRD5A2 genes in twenty Iranian phenotypic females with 46,XY DSD. All exons in and genes were subjected to PCR amplification followed by sequencing. Of 20 identified 46, XY DSD patients, one had a homozygous missense 17β-HSD3 mutation Ser65Leu (c.194C > T). We found 1 SRD5A2 novel homozygous missense mutation of Tyr242Asp (c.891T > G) in exon 5, which in-silico analyses revealed that this mutation may have deleterious impact on ligand binding site of SRD5A2 protein. Three other individuals harbored 17β-HSD3 deficiencies without identified mutations. SRD5A2 and 17β-HSD3 mutations are found in 10% of 46, XY DSD Iranian patients.
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http://dx.doi.org/10.1080/15513815.2020.1745974DOI Listing
May 2020

MAML1 promotes ESCC aggressiveness through upregulation of EMT marker TWIST1.

Mol Biol Rep 2020 Apr 16;47(4):2659-2668. Epub 2020 Mar 16.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Mastermind-like 1 (MAML1) is the main transcriptional co-activator of Notch signaling pathway. It plays essential roles in several pathways including MEF2C, p53, Nf-кB and Wnt/β-catenin. TWIST1 is known as a regulator of epithelial mesenchymal transition (EMT), which is considered as a primary step in promotion of tumor cell metastasis. Since concomitant expression of these genes was observed in tumors, our aim in this study was to elucidate the linkage between MAML1 and TWIST1 co-overexpression in esophageal squamous cell carcinoma (ESCC).

Results: While MAML1 silencing significantly down-regulated TWIST1, its ectopic expression up-regulated TWIST1 expression in both mRNA and protein levels in KYSE-30 cells. Expression of mesenchymal markers was increased significantly after MAML1 and TWIST1 ectopic expression, while epithelial markers expression was significantly decreased after silencing of both genes. Concomitant protein expression of MAML1 and TWIST1 was significantly observed in ESCC patients. Enforced expression of TWIST1 had no impact on MAML1 gene expression in KYSE-30 cells.

Conclusion: The results clearly suggest transcriptional regulation of TWIST1 by MAML1 transcription factor in ESCC cells KYSE-30. Since TWIST1 is known as an EMT inducing marker, our results may revealed the mastermind behind TWIST1 function and introduced MAML1 as an upstream master regulator of TWIST1 and EMT in KYSE-30 cells.
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http://dx.doi.org/10.1007/s11033-020-05356-zDOI Listing
April 2020

Primary Angle Closure Glaucoma-associated Genetic Polymorphisms in Northeast Iran.

J Ophthalmic Vis Res 2020 Jan-Mar;15(1):45-52. Epub 2020 Feb 2.

Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose: To evaluate the association of five different polymorphisms from a genome-wide-associated study with susceptibility to glaucoma in the northeast Iranian population.

Methods: Hundred and thirty patients with primary angle closure glaucoma (PACG) and 130 healthy controls were genotyped for the polymorphic regions with the aid of tetra-amplification refractory mutation system-polymerase chain reaction. The association of these variants with the disease susceptibility was measured statistically with the logistic regression method.

Results: Hundred and thirty patients with PACG (53 males, 77 females) with a mean age of 64.5 6.2 years and 130 healthy control subjects (51 males, 79 females) with a mean age of 64.0 5.7 years were selected for evaluation. There was a significant association between rs3816415 ( = 0.005), rs736893 ( 0.001), rs7494379 ( 0.001), and rs1258267 ( = 0.02) with PACG susceptibility. This association could not be shown for rs3739821.

Conclusion: It was revealed that studied variants in and genes can contribute to the incidence of PACG. Additional studies in other populations are needed to evaluate .
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http://dx.doi.org/10.18502/jovr.v15i1.5942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001019PMC
February 2020

The Role of Interleukin-4 and 13 Gene Polymorphisms in Allergic Rhinitis: A Case Control Study.

Rep Biochem Mol Biol 2019 Jul;8(2):111-118

Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Allergic Rhinitis (AR) is an IgE-mediated inflammatory disorder with high morbidity rates. The eitiology of this disease is understood to occur from a complex interaction between genetic and environmental factors. T helper type 2 cells have been shown to have a crucial role in atopic disease due to their production of the cytokines, intelukin and , involved in inflammation. Research has shown single nucleotide polymorphisms (SNP) of the and genes to be associated increased levels of IgE and with allergic diseases such as, allergic rhinitis, asthma, and atopic dermatitis. Specifically, the rs2243250 SNP of IL-4 and the rs20541 SNP of have been shown to be associated with AR.

Methods: A case-control study was designed to investigate the relationship between the two SNPs rs2243250 and rs20541 with the incidence of AR. The SNPs were examined in patients with AR and healthy controls (86 patients and 86 controls). Blood samples were collected and DNA was extracted to evaluate the SNPs by RFLP-PCR.

Results: Recessive analysis model of the gene (GG vs. AA+AG) revealed that the GG genotype was more common in AR patients (P=0.36) )OR=0.8 [81% CI 0.38-1.6]). For the gene (TC vs. TT+CC), the TC genotype was more common in AR patients (P = 0.0022)) OR=0.71 [60% CI 1.41-5.02]). Furthermore, in the IL-4 gene, the 590 T>C polymorphism had a significant association with AR. However, no association was found between AR and the rs20541 polymorphism.

Conclusion: Our findings suggest that the polymorphism (rs20541, Exo 4, G>A, Arg130Gln) and IL-4 polymorphism (rs2243250= C-590T, promoter, T>C) are co-associated with AR and sensitivity to aeroallergens. However, this study used a cohort of AR patients and healthy controls from the northeast of Iran. Given the influence of ethnicity and environment on genetics, further investigation is needed to elucidate the role of SNPs in and in AR among different populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844616PMC
July 2019

Ovarian cancer stem cells and targeted therapy.

J Ovarian Res 2019 Dec 6;12(1):120. Epub 2019 Dec 6.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Ovarian cancer has the highest ratio of mortality among gynecologic malignancies. Chemotherapy is one of the most common treatment options for ovarian cancer. However, tumor relapse in patients with advanced tumor stage is still a therapeutic challenge for its clinical management.

Main Body: Therefore, it is required to clarify the molecular biology and mechanisms which are involved in chemo resistance to improve the survival rate of ovarian cancer patients. Cancer stem cells (CSCs) are a sub population of tumor cells which are related to drug resistance and tumor relapse.

Conclusion: In the present review, we summarized the recent findings about the role of CSCs in tumor relapse and drug resistance among ovarian cancer patients. Moreover, we focused on the targeted and combinational therapeutic methods against the ovarian CSCs.
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http://dx.doi.org/10.1186/s13048-019-0588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896744PMC
December 2019

Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

Am J Hum Genet 2019 12 21;105(6):1294-1301. Epub 2019 Nov 21.

Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, Singapore 138648, Republic of Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Department of Medical Genetics, Koç University, School of Medicine, 34010 Topkapı, Istanbul, Turkey. Electronic address:

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113 and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113 stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904794PMC
December 2019

Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression.

J Psychopharmacol 2019 11 26;33(11):1364-1376. Epub 2019 Sep 26.

Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The relationship between depression and increased oxidative stress is well known. DNA damage by oxidation factors is an important cause of the aging process in psychiatric disorders.

Aims: Owing to the scarcity of human studies and high inconsistencies in studies of the effects of antidepressants on DNA damage, the current study was undertaken to investigate the effects of depression and its treatment on DNA damage.

Methods: In a 15-week open-label study of citalopram ( = 25) and sertraline ( = 20), levels of DNA damage were measured by comet assay, proinflammatory (Interlukin-6 (IL-6)) and oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)) markers by ELISA, and gene expression of base excision repair enzymes (8-oxoguanine glycosylase (OGG1) and poly (ADP)-ribose polymerase-1 (PARP1)) by quantitative real-time polymerase chain reaction in healthy control patients ( = 14), with depression at the baseline and the same patients after week 15.

Results: DNA damage, 8-OHdG, IL-6 and expression of PARP1 were elevated in patients with depression compared with the healthy controls ( < 0.001). Selective serotonin reuptake inhibitor (SSRI) therapy could significantly reduce the depression score ( < 0.01), DNA damage ( < 0.001), as well as 8-OHdG and IL-6 ( < 0.0001). Nevertheless, the expression of PARP1 and OGG1 showed no significant changes after treatment.

Conclusions: This is the first study on the effect of SSRIs on the DNA damage and some of the repair enzymes in depression. Based on the results, depression can cause increased DNA damage. This damage is followed by activation of compensatory mechanisms whereby the expression of DNA damage repair enzymes is elevated. Finally, the treatment of psychiatric disorder by antidepressants can lower the level of oxidative DNA damage.
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http://dx.doi.org/10.1177/0269881119874461DOI Listing
November 2019

Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1.

Immunobiology 2019 11 6;224(6):728-733. Epub 2019 Sep 6.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Purpose: Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3.

Methods: In this study, we performed Sanger sequencing ofAIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1.

Results: After analyzing 14AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE, including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients.

Discussion: According to our results, sequencing analysis ofAIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1.
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http://dx.doi.org/10.1016/j.imbio.2019.09.004DOI Listing
November 2019
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