Publications by authors named "Mohsen Ghadami"

27 Publications

  • Page 1 of 1

Variable Clinical Manifestations of COVID-19: Viral and Human Genomes Talk.

Iran J Allergy Asthma Immunol 2020 Oct 18;19(5):456-470. Epub 2020 Oct 18.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

The new coronavirus, known as "SARS-CoV-2"; is the cause of one of the most prevalent infectious viral diseases that was recently announced pandemic by the world health organization. Ongoing research in the fields of prevention, management, and therapy establishes a functional scaffold for clinics during the time of crisis. To obtain this goal, it is necessary that all pathophysiologic aspects of COVID-19 from infection to predisposing backgrounds of infection be identified, so that all the ambiguities of researchers regarding transmission mechanisms, variable clinical manifestation, and therapeutic response can be solved. Here, we firstly discuss about the homology screening between nCoV-2019 and beta-coronavirus family using phylogenetic analyses. Secondly, we analyzed the viral motifs to show that viral entry into the host cells requires a primary activation step performed by FURIN and FURIN-like-mediated enzymatic cleavage on the structural glycoprotein. The cleavage increases viral performance by 1000 folds. We then present a comprehensive view on host cells and the significance of gene variants affecting activation enzymes, supportive entry, and spread mechanisms in humans including renin-angiotensin-aldosterone system (RAAS) a pathway results in certain phenotypes or exacerbate infection-related phenotypes in different organs, hence causes variable clinical manifestations. This is followed by discussing about the importance of personalized medicine in nCoV-2019 exposure. Moreover, chemical drugs prescribed for individuals affected with COVID-19, as well as genes involved in drug transport and metabolisms are reviewed as a prelude to drug response. Finally, we suggest some therapeutic approaches developed based on new methods and technology such as anti-sense therapy and antibodies.
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http://dx.doi.org/10.18502/ijaai.v19i5.4461DOI Listing
October 2020

Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy.

J Hum Genet 2021 Apr 10;66(4):401-407. Epub 2020 Oct 10.

Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
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http://dx.doi.org/10.1038/s10038-020-00853-2DOI Listing
April 2021

Investigation of promoter methylation of FSCN1 gene and FSCN1 protein expression in differentiated thyroid carcinomas.

Mol Biol Rep 2020 Mar 18;47(3):2161-2169. Epub 2020 Feb 18.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Poursina St, Tehran, Iran.

FSCN1 gene encodes an actin-bundling protein, FSCN1, which is involved in formation of actin-based structures that contribute to cell migration. High levels of FSCN1 expression is observed in cells with extended membranes and protrusions. Moreover, up-regulation of FSCN1 has been reported in several epithelial carcinomas. Therefore, FSCN1 is thought to play a role in cell movement and invasion. However, the mechanism behind FSCN1 up-regulation is not known. We investigated the expression of FSCN1 using immunohistochemistry. Methylation-specific PCR was adopted to analyze the methylation status of FSCN1 promoter as a potential regulatory mechanism in FSCN1 expression. The samples included papillary thyroid carcinoma, follicular thyroid carcinoma and goiter samples (controls). Methylation of FSCN1 promoter was observed in 50% of follicular, 48.6% of papillary and 60% of controls. The promoter was unmethylated in 16.7% of follicular samples, 5.7% of papillary samples and 26.7% of controls. In the remaining 33.3% of follicular and 45.7% of papillary samples as well as 13.3% of controls, both methylated and unmethylated alleles were amplified, a condition referred to as semi-methylation. The results showed that FSCN1 promoter was significantly hypomethylated in papillary cases while the methylation status was not significantly altered in follicular cases. On the other hand, FSCN1 was expressed in only nine papillary samples. Regarding protein expression and methylation status, we suggest that hypomethylation of FSCN1 promoter in papillary thyroid carcinoma does not lead to overexpression of FSCN1 and that there might be other regulatory mechanisms involved in FSCN1 up-regulation.
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http://dx.doi.org/10.1007/s11033-020-05315-8DOI Listing
March 2020

RPE65 and retinal dystrophy: Report of new and recurrent mutations.

J Gene Med 2020 03 19;22(3):e3154. Epub 2020 Jan 19.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Bachground: Leber congenital amaurosis (LCA) is a severe and congenital or early onset form of inherited retinitis pigmentosa (RP). To date, approximately 25 genes have been introduced in relation to LCA. In this regard, retinal pigment epithelium-specific 65 kDa (RPE65) is a well-known gene mutation that plays a role in the pathogenesis of 5-10% of LCA cases.

Methos: Two individuals fromseparate families were subjected to ehole exome sequencing (WES). Causativevariants were searched further assessed using Sanger sequencing.

Results: Here, two families with mutations in the RPE65 gene show severe and early onset LCA, as expected. In addition to the characterization of the phenotype, by reporting a new mutation (c.1451-1G>A), we further expand the mutation spectrum of RPE65. Likewise, as an interesting aspect of our study, we report on a previously reported RP-linked mutation associated with severe early onset LCA (c.T200G:p.L67R).

Conclusions: Considering this variant in different populations, it is likely that it represents a hotspot and affects the function of the coded protein. The variable expressivity of the phenotype can be assumed by the presence of the modifier allele(s) as a result of a different genetic background or the effect of different environments on phenotype expression.
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http://dx.doi.org/10.1002/jgm.3154DOI Listing
March 2020

Evaluation of the Prevalence of Exons 1 And 10 Polymorphisms of Gene and Its Relationship with IVF Success.

J Reprod Infertil 2019 Oct-Dec;20(4):218-224

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Luteinizing hormone receptor gene shows four nonsynonymous polymorphisms within the exons. Three of these polymorphisms, . rs4539842 (an insertion of 6bp CTGCAG at nucleotide position 54), rs12470652 (c.827A>G/p.Asn 291Ser), and rs2293275(c.935G>A/p.Ser312Asn) have been studied more frequently. Beside other hormones, LH and FSH have an important role in production of competent oocyte and female fertility. Therefore, the objective of the current study was to investigate the prevalence of exons 1(rs4539842) and 10(rs12470652, rs2293275) polymorphisms of the gene and its relationship with successful IVF in Iranian infertile women.

Methods: SNPs in exons 1 and 10 were analyzed in 100 women of two equally sized groups of IVF failure and IVF success women using genomic DNA. For polymorphisms in exon 10, PCR and direct sequencing were used and for the polymorphism in exon 1, RFLP technique was used. The RFLP technique is confirmed by sequencing.

Results: Our results showed significant difference in allelic frequency of SNP rs2293275 among IVF successful and IVF failure groups (p=0.001). For this variation, AA genotype (A allele) was shown to have protective effect against IVF failure (p=0.03 and OR=0.04), while GG genotype (G allele) was a susceptive genotype to IVF failure (p=0.003 and OR=3.88).Allelic frequency of SNP rs4539842 also showed significant difference between the two groups (p=0.0025). For this SNP, subjects with no 6bp insertion (homozygote deletion genotype) were susceptible to failure in IVF (p=0.009 and OR=2.93).

Conclusion: It has been revealed that two common SNPs (rs4539842 and rs2293275) in the gene are associated with the outcome of IVF in Iranian infertile women. Thus, these two SNPs can be suggested to be used as predictors for IVF outcome in Iranian population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928402PMC
January 2020

Cell Free Tumoral DNA Versus Paraffin Block Epidermal Growth Factor Receptor Mutation Detection in Patients with Non-Small Cell Lung Cancer.

Asian Pac J Cancer Prev 2019 Dec 1;20(12):3591-3596. Epub 2019 Dec 1.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran. Iran.

Increasing knowledge about the molecular profile of tumors has led to personalized treatment for achieving better outcomes in patients with nonsmall cell lung cancer (NSCLC). Currently, finding exact somatic genomic changes of tumor has gained great importance. On the other hand, crescendoing needs to actual tumor tissue at different time points during cancer treatment may produce major discomfort for NSCLC patients. Tumor genomes can be reconstructed by information obtained from circulating cell-free deoxyribonucleic acid (cfDNA) of peripheral blood. cfDNA may be represented as a suitable alternative test  for epidermal growth factor receptor (EGFR) mutation detection in these patients. This study aimed to assess validity of cfDNA in somatic EGFR mutation identification in Iranian NSCLC cases.

Methods: Somatic mutation of EGFR gene was studied in both tissue specimens and plasma. Then, mutations were detected by polymerase chain reaction(PCR) and sequencing.

Results: We observed a high concordance (90%) between tissue samples and cfDNA for EGFR gene mutation.  The sensitivity, accuracy, and positive precision value were 90%, 90% and 100%, respectively. A false negative rate of 10% was also demonstrated in this study.

Conclusion: We established sensitive methods for detecting EGFR gene mutation which may be very useful in clinical practice.
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http://dx.doi.org/10.31557/APJCP.2019.20.12.3591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173361PMC
December 2019

Circulating free DNA concentration as a marker of disease recurrence and metastatic potential in lung cancer.

Clin Transl Med 2019 Apr 18;8(1):14. Epub 2019 Apr 18.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Plasma circulating cell-free (cf) DNA is regarded as a source of tumor DNA. Based on availability of blood tissue for the purposes of early detection of cancer and patients' follow-up, several studies have evaluated concentration of cf DNA in cancer patients in association with tumor features. In the present study, we assessed concentration of cf DNA in lung cancer patients with two commercial kits (MN and QIAGEN) to find whether it can be used as a prognostic biomarker.

Results: Primary cf DNA concentrations as measured by QIAGEN kit was significantly higher in patients who died in the follow-up period compared with alive patients (P = 0.007). Moreover, the concentrations as measured by both methods were higher in patients who experienced recurrence in the follow-up period compared with patients without recurrence (P = 0.008 and 0.007 for MN and QIAGEN kits respectively). Significant associations were also found between cf DNA concentrations and tumor stage (P = 0.005 and 0.02 for MN and QIAGEN kits respectively). Notably, cf DNA concentration was higher in metastatic tumors compared with non-metastatic tumors in association with number of involved organs. Based on the AUC values, both kits could differentiate metastatic cancers from non-metastatic ones with accuracy of 98%.

Conclusions: The current study highlights the accuracy of cf DNA concentrations for prediction of disease course in lung cancer patients.
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http://dx.doi.org/10.1186/s40169-019-0229-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473013PMC
April 2019

The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long-term follow-up and genetic analysis.

Pediatr Allergy Immunol 2019 06 15;30(4):469-478. Epub 2019 May 15.

Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Hyper-IgE syndromes (HIES) are distinct diseases characterized by recurrent cutaneous and lung infections, eczema, and elevated serum IgE level.

Methods: In this study, clinical manifestations, immunologic findings, and genetic studies of all patients with HIES in the Iranian national registry database were evaluated.

Results: A total of 129 HIES patients with a median age of 14.0 (9.0-24.0) years were followed up for a total of 307.8 patient-years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3-deficient patients was higher than in patients with DOCK8 mutation (P = 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3-deficient cases compared to patients with DOCK8 deficiency (P = 0.001 and P = 0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than in patients with DOCK8 gene mutation (P = 0.02). The eosinophils' count was enhanced in patients with DOCK8 deficiency than in patients with STAT3 gene defects (P = 0.02).

Conclusion: Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency, investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities.
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http://dx.doi.org/10.1111/pai.13043DOI Listing
June 2019

Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency.

J Allergy Clin Immunol 2018 04 12;141(4):1450-1458. Epub 2017 Sep 12.

Acquired Immunodeficiency Research Center, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited.

Objectives: This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically.

Methods: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients.

Results: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs.

Conclusions: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.
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http://dx.doi.org/10.1016/j.jaci.2017.06.049DOI Listing
April 2018

Association of SP-B gene 9306 A/G polymorphism (rs7316) and risk of RDS.

J Matern Fetal Neonatal Med 2018 Nov 7;31(22):2965-2970. Epub 2017 Aug 7.

a Maternal, Fetal and Neonatal Research Center , Imam Khomeini Hospital Complex, Tehran University of Medical Sciences , Tehran , Iran.

Background: Respiratory distress syndrome (RDS) is a severe pulmonary disease predominantly affects preterm newborns. Polymorphisms of surfactant-protein genes have been mostly evaluated as the candidate contributors in genetics of RDS. However the results are divers in different studies. We aimed at investigating the association of surfactant protein B (SPB) gene 9306 A/G polymorphism (rs7316) with RDS development.

Method: Three hundred and eighty newborns with gestational age of less than 34 weeks were included in a multicenter case-control study. Respiratory distress (RD) was scored according to Downes' scoring system. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping.

Result: One hundred and eighty-four neonates showed RDS and 196 did not. Gestational age (GA) was significantly lower in the RDS group compared with the controls. AA genotype and A allele were found more frequently in the RDS group than the controls (96.2% versus 63.8% and 98.1% versus 80.6%, respectively) (p =.0001).

Conclusions: This is the first report of association of SFTPB rs7316 polymorphism with RDS development in Iranian newborns. The current study suggests that GA <28-weeks is the most important factor in predisposition to RDS. Genetic background in terms of SP-B gene might be involved in predisposition to RDS in premature neonates.
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http://dx.doi.org/10.1080/14767058.2017.1359829DOI Listing
November 2018

Demethylation and alterations in the expression level of the cell cycle-related genes as possible mechanisms in arsenic trioxide-induced cell cycle arrest in human breast cancer cells.

Tumour Biol 2017 Feb;39(2):1010428317692255

1 Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Arsenic trioxide (AsO) has been used clinically as an anti-tumor agent. Its mechanisms are mostly considered to be the induction of apoptosis and cell cycle arrest. However, the detailed molecular mechanisms of its anti-cancer action through cell cycle arrest are poorly known. Furthermore, AsO has been shown to be a potential DNA methylation inhibitor, inducing DNA hypomethylation. We hypothesize that AsO may affect the expression of cell cycle regulatory genes by interfering with DNA methylation patterns. To explore this, we examined promoter methylation status of 24 cell cycle genes in breast cancer cell lines and in a normal breast tissue sample by methylation-specific polymerase chain reaction and/or restriction enzyme-based methods. Gene expression level and cell cycle distribution were quantified by real-time polymerase chain reaction and flow cytometric analyses, respectively. Our methylation analysis indicates that only promoters of RBL1 (p107), RASSF1A, and cyclin D2 were aberrantly methylated in studied breast cancer cell lines. AsO induced CpG island demethylation in promoter regions of these genes and restores their expression correlated with DNA methyltransferase inhibition. AsO also induced alterations in messenger RNA expression of several cell cycle-related genes independent of demethylation. Flow cytometric analysis revealed that the cell cycle arrest induced by AsO varied depending on cell lines, MCF-7 at G1 phase and both MDA-MB-231 and MDA-MB-468 cells at G2/M phase. These changes at transcriptional level of the cell cycle genes by the molecular mechanisms dependent and independent of demethylation are likely to represent the mechanisms of cell cycle redistribution in breast cancer cells, in response to AsO treatment.
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http://dx.doi.org/10.1177/1010428317692255DOI Listing
February 2017

Association of SP-C gene codon 186 polymorphism (rs1124) and risk of RDS.

J Matern Fetal Neonatal Med 2017 Nov 24;30(21):2585-2589. Epub 2016 Nov 24.

a Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences , Tehran , Iran.

Background: Respiratory distress syndrome (RDS) is a severe pulmonary disease that mainly affects preterm neonates. Surfactant-protein genes' polymorphisms have been mostly evaluated as the candidate contributors in genetics of RDS. However, the results are diverse in different populations. We aimed at investigating the association of rs1124 with RDS development.

Method: Three hundred and thirty five preterm neonates were enrolled in a multicenter case-control study. Respiratory distress (RD) was scored according to Downes' scoring system. Genotyping was performed by PCR-RFLP method.

Result: One hundred and sixty six neonates showed RDS and 169 did not. Gestational age (GA) was significantly lower in RDS group compared to the controls. In female preterm newborns, AA genotype was found more frequently in RDS group. In RDS group, AA genotype was also associated with milder RD irrespective of gender. In neonates who were born 28-34 weeks, RD appeared to be more severe in the RDS group and males.

Conclusions: This is the first report of association of SFTPC rs1124 polymorphism with RDS development in Iranian newborns. The current study suggests that GA <28-weeks is the most important factor in predisposition to RDS. AA genotype is also, a predisposing factor for the development of RDS in female preterm infants.
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http://dx.doi.org/10.1080/14767058.2016.1256994DOI Listing
November 2017

Investigation of ITGB2 gene in 12 new cases of leukocyte adhesion deficiency-type I revealed four novel mutations from Iran.

Arch Iran Med 2015 Nov;18(11):760-4

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Leukocyte adhesion deficiency type I (LAD-I) is a rare, autosomal recessive inherited immunodeficiency disease. LAD-I is caused by mutations in the ITGB2 gene and characterized by recurrent severe bacterial infections, as well as impaired wound healing with lack of pus formation.

Methods: In this study, we investigated ITGB2 gene mutations in 12 patients and their parents. Genomic DNA was extracted from whole blood samples. All coding regions of the ITGB2 gene were amplified using PCR and followed by direct sequencing.

Results: Genetic analysis revealed 12 different homozygous mutations, including six missense (c.382G>A, c.2146G>C, c.715G>A, c.691G>C, c.1777C and new c.1686C>A), two new nonsense (c.1336G>T and c.1821C>A), three-frame shift (c.1143delc, c.1907delA and new c.474dupC) and a splice site (c.1877+2T>C). Flow cytometry analysis of CD11/CD18 expression on neutrophils revealed defect in CD18 in all twelve cases (1.4% to 42%), CD11a in ten cases (0.1% to 26.7%), CD11b in nine cases (1.2% to 58.8%), and CD11c in all cases (0 % to 18.1%). The patients' parents were both heterozygous carriers.

Conclusion: Our findings showed four new mutations in the ITGB2 gene. These results can be used for decisive genetic diagnosis, genetic counseling, as well as  prenatal diagnosis for all patients who are suspended to LADI.
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http://dx.doi.org/0151811/AIM.006DOI Listing
November 2015

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Hum Mol Genet 2015 Oct 23;24(20):5697-710. Epub 2015 Jul 23.

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 19857, Iran, Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.
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http://dx.doi.org/10.1093/hmg/ddv286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581600PMC
October 2015

Study of cytomegalovirus infection in idiopathic infertility men referred to Shariati hospital, Tehran, Iran.

Iran J Reprod Med 2014 Feb;12(2):151-4

School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran. ; Zoonosis Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Cytomegalovirus (CMV) is a prevalent infection in humans. Recent studies have shown the role of CMV infection in male infertility disorder.

Aim: Here we aimed to study the role of CMV infection in men with idiopathic infertility.

Materials And Methods: We performed a case-control study of CMV serology in 200 patients attending male infertility clinic of a university hospital. There were 154 men diagnosed with infertility and 46 men without infertility. The patients were asked to donate their sperm, blood, and urine. The presence of CMV infection was studied using quantitative polymerase chain reaction.

Results: CMV infection was present in 25 of all the studied participants. Controls had a higher sperm count and sperm motility and sperm morphology compared to patients. There were no significant differences in the studied variables between those with and without CMV infection, nor in patients, neither in controls. Sperm morphology was negatively correlated with cigarette smoking (r=-0.15; p<0.03). Even though the prevalence of CMV infection was higher in patients with infertility in control and patient (5/46 vs. 20/154) respectively, this was not statistically significant.

Conclusion: We did not show a significant role for CMV infection in male infertility. Based on the previous studies, it could be assumed that CMV infection is an important part of the male infertility and its treatment would improve the sperm quality, however this was not confirmed by the present study.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009566PMC
February 2014

Prenatal diagnosis of leukocyte adhesion deficiency type-1 (five cases from iran with two new mutations).

Iran J Allergy Asthma Immunol 2014 Feb;13(1):61-5

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Leukocyte adhesion deficiency type-1(LAD-1) is one of the immunodeficiency autosomal recessive diseases that results from mutation in integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) ITGB2 gene. The aim of this study was to investigate molecular prenatal diagnosis of LAD-1. Four pregnant women with five fetuses (one pregnancy was twin) with clinical and laboratory diagnosis of LAD-1 in their previous children were studied. The chorionic villus sampling (CVS) was obtained when mothers were in 10-12th weeks of gestation. Mutation analysis of ITGB2 gene for affected children revealed 3 misssense mutations (c.382G>A, a novel mutation, c.2146G>C, and c.715G>A) and one splice site novel mutation (c.1877+2G>A). All of Parents were heterozygous for these mutations. Consideration of affected gene regions for five CVS samples showed two homozygotes and one heterozygote for mutant allele and two homozygotes for normal allele. Interestingly, one of the twin fetuses was affected and another was normal. Briefly, two cases of CVS samples were affected and three cases of remained CVS samples were unaffected.This is the first report of prenatal diagnosis of LAD-1 from Iran with two new mutations that can be used for genetic and prenatal diagnosis for all patients suspected to LAD1 and can be helpful to prevent the birth of affected children with LAD-1. This abstract presented in the second international congress of Immunology, Asthma and Allergy, Tehran, Iran 2013.
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February 2014

Essential genes in thyroid cancers: focus on fascin.

J Diabetes Metab Disord 2013 Jul 1;12(1):32. Epub 2013 Jul 1.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 5th floor, Dr, Shariati Hospital, North Kargar Ave, Tehran, Iran.

Although thyroid cancers are not among common malignancies, they rank as the first prevalent endocrine cancers in human. According to the results of published studies it has been shown the gradual progress from normal to the neoplastic cell in the process of tumor formation is the result of sequential genetic events. Among them we may point the mutations and rearrangements occurred in a group of proto-oncogenes, transcription factors and metastasis elements such as P53, RAS,RET,BRAF, PPARγ and Fascin. In the present article,we reviewed the most important essential genes in thyroid cancers, the role of epithelial mesenchymal transition and Fascin has been highlighted in this paper.
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http://dx.doi.org/10.1186/2251-6581-12-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983713PMC
July 2013

MicroRNAs networks in thyroid cancers: focus on miRNAs related to the fascin.

J Diabetes Metab Disord 2013 Jul 1;12(1):31. Epub 2013 Jul 1.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 5th floor, Dr, Shariati Hospital, North Kargar Ave, Tehran, Iran.

miRNAs are non coding ribonucleic acids which are protected with respect to evolution, and have a length of 18-25 nucleotides. microRNAs control the gene expression after transcription, through mRNA destruction or translation processing, and therefore participate in arrangement of the physiologic and pathologic cellular processes; They also may act as oncogene or tumor suppressors. Altered expression of a number of microRNAs is reported in process of progression and metastasis of thyroid cancers. Therefore, identification of these microRNAs may shed a light to oncogenesis pathway of thyroid cancers and their metastasis. In addition, microRNAs might apply as potential biological markers in diagnosis and treatment of thyroid cancers. The changes made in miRNAs profile of thyroid cancers are reviewed in this paper.
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http://dx.doi.org/10.1186/2251-6581-12-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976609PMC
July 2013

Bone marrow transplantation restores follicular maturation and steroid hormones production in a mouse model for primary ovarian failure.

PLoS One 2012 7;7(3):e32462. Epub 2012 Mar 7.

Endocrine and Metabolism Research Institute, and Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.

Recent studies suggest that bone marrow stem cells (BMSCs) are promising grafts to treat a variety of diseases, including reproductive dysfunction. Primary ovarian failure is characterized by amenorrhea and infertility in a normal karyotype female, with an elevated serum level of follicle-stimulating hormone (FSH) and a decrease level of estrogen caused by a mutation in FSH receptor (FSHR) gene. Currently, there is no effective treatment for this condition. The phenotype of FSHR (-/-) mouse, FORKO (follitropin receptor knockout), is a suitable model to study ovarian failure in humans. Female FORKO mice have elevated FSH, decreased estrogen levels, are sterile because of the absence of folliculogenesis, and display thin uteri and small nonfunctional ovaries. In this study, we determined the effects of BMSC transplantation on reproductive physiology in this animal model. Twenty four hours post BMSC transplantation, treated animals showed detectable estroidogeneic changes in daily vaginal smear. Significant increase in total body weight and reproductive organs was observed in treated animals. Hemotoxylin and eosin (H&E) evaluation of the ovaries demonstrated significant increase in both the maturation and the total number of the follicles in treated animals. The FSH dropped to 40-50% and estrogen increased 4-5.5 times in the serum of treated animals compared to controls. The FSHR mRNA was detected in the ovaries of treated animals. Our results show that intravenously injected BMSCs were able to reach the ovaries of FORKO mice, differentiate and express FHSR gene, make FSHR responsive to FSH, resume estrogen hormone production, and restore folliculogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032462PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296713PMC
August 2012

Two cases of syndromic neutropenia with a report of novel mutation in G6PC3.

Iran J Allergy Asthma Immunol 2011 Sep;10(3):227-30

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Severe congenital neutropenia (SCN) is a rare primary immunodeficiency. Different genes are found to be associated with SCN, including ELA2, HAX1, WAS, GFI1, G-CSFR. Also, recently G6PC3 as a rare gene in SCN has been reported. Patients with G6PC3 often have cardiac and/or urogenital malformations. Two patients with persistent severe neutropenia, recurrent infections and maturation arrest at promyelocyte-myelocyte stage in their bone marrow were assessed in this study. Both patients showed structural heart disease and one of them also showed urogenital anomaly. Sequence analyses of G6PC3 in 2 patients revealed two different homozygous mutations, one in exon 6 (Asn 313 fs), and the other in exon 3 (Ser 139 Met), the latter is a new mutation which has not been reported in previous studies. It can be concluded that G6PC3 is one of the responsible gene for SCN in Iranian patients. Based on the results, a new mutation in G6PC3 observed in one patient.
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http://dx.doi.org/010.03/ijaai.227230DOI Listing
September 2011

Familial ankyloglossia (tongue-tie): a case report.

Acta Med Iran 2010 Mar-Apr;48(2):123-4

Research Center for Human Genetics, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Ankyloglossia (tongue-tie) is a congenital anomaly with a prevalence of 4-5% and characterized by an abnormally short lingual frenulum. For unknown reasons the abnormality seems to be more common in males. The pathogenesis of ankyloglossia is not known. The authors report a family with isolated ankyloglossia inherited as an autosomal dominant or recessive trait. The identification of the defective gene(s) in these patients might reveal novel information on the pathogenesis of this disorder.
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January 2011

A SNP in the ABCC11 gene is the determinant of human earwax type.

Nat Genet 2006 Mar 29;38(3):324-30. Epub 2006 Jan 29.

Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait.
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http://dx.doi.org/10.1038/ng1733DOI Listing
March 2006

Isolated congenital anosmia with morphologically normal olfactory bulb in two Iranian families: a new clinical entity?

Am J Med Genet A 2004 Jun;127A(3):307-9

Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Congenital total loss of the sense of smell occurs as a part of a syndrome or isolated anosmia. Kallmann syndrome is the most well known congenital anosmia associated with hypogonadotropic hypogonadism. Isolated congenital anosmia (ICA) is a very rare condition and appears to be due to changes in the olfactory epithelium or to aplasia of the olfactory nerve, bulb, and tract. Here we report two unrelated Iranian families with ICA. One family consisted of nine affected members, and the other family contained three affected members. Clinical history, physical examination, and smell testing by intravenous injection of combined vitamins (Alinamin trade mark, Takeda Pharmaceutical Co. Ltd., Japan) confirmed the disease in each affected member. No signs of hypogonadism or other neurological disorders were observed in any affected members. Family analysis with the complete ascertainment method under assumption of the same condition in the two families suggested that the disease is not inconsistent with an autosomal dominant mode with incomplete penetrance. The inheritance in one family appears unusual, i.e., there were no affected individuals in the third generation. When only two upper generations in the family are concerned, the segregation ratio was 0.39 +/- 0.11. Male-to-male transmissions were observed and both sexes were affected in both families. Magnetic resonance imaging (MRI) of the olfactory bulb and sulcus revealed no evidence of morphological changes in all affected members, suggesting that these patients have either a defect in the olfactory epithelium or a functional defect in the olfactory cortex.
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http://dx.doi.org/10.1002/ajmg.a.30025DOI Listing
June 2004

Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family.

J Hum Genet 2002 ;47(8):395-9

Department of Human Genetics, Nagasaki University School of Medicine, Sakamoto, Nagasaki, Japan.

Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) comprises a group (DFNA1, DFNA6, DFNA14, and DFNA38) of hearing disorders affecting only frequencies below 2000 Hz, and is often associated with tinnitus. An LFSNHL locus has recently been assigned to chromosome 4p16, and mutations in WFS1, the causative gene for Wolfram syndrome, have been found to cause LFSNHL in families with DFNA6, DFNA14, or DFNA38. We performed a genome-wide linkage analysis of a Japanese family in which 20 members were affected with LFSNHL and obtained a maximum LOD score of 5.36 at a recombination fraction of 0.05 ( P = 1.00) at the D4S2983 locus on 4p16. Haplotype analysis revealed that the disease locus mapped to between D4S2366 and D4S2983. Mutation analysis revealed a novel missense mutation (K634T) in WFS1. We thus concluded that the LFSNHL in this family was caused by the WFS1 mutation. The mutation observed (K634T) was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein, wolframin, and was hitherto undescribed. This unique mutation site in our patients is likely related to their milder phenotype (lacking tinnitus) compared with those of six previous DFNA6/14 patients with WFS1mutations. It is likely that a genotype-phenotype correlation is also applicable in the case of DFNA6/14/38.
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http://dx.doi.org/10.1007/s100380200057DOI Listing
October 2002

Mapping of the wet/dry earwax locus to the pericentromeric region of chromosome 16.

Lancet 2002 Jun;359(9322):2000-2

Department of Human Genetics, Nagasaki University School of Medicine, Nagasaki, Japan.

Human earwax is a one-gene trait comprising two phenotypically distinct forms--wet and dry. This trait is attributed to secretory products of the ceruminous apocrine glands, and frequencies of phenotypes vary between ethnic groups. We did linkage analysis of eight Japanese families segregating earwax dimorphism. We assigned the earwax locus within a approximately 7.42-cM region between the loci D16S3093 and D16S3080 on chromosome 16p11.2-16q12.1, with a maximum two-point LOD score of 11.15 (theta;=0.00) at the locus D16S3044. Identification of the earwax locus could contribute to further anthropogenetic studies and physiological and pathological understanding of the apocrine-gland development.
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http://dx.doi.org/10.1016/S0140-6736(02)08835-9DOI Listing
June 2002

Camurati-Engelmann disease type II: progressive diaphyseal dysplasia with striations of the bones.

Am J Med Genet 2002 Jan;107(1):5-11

Department of Radiology, Nasu-Chuou Hospital, Tochigi, Japan.

We recently found mutations of the transforming growth factor beta 1 (TGF-beta1) gene (TGFB1) in 9 families, in which progressive diaphyseal dysplasia (Camurati-Engelmann disease) is segregating [Kinoshita et al., 2000: Nat Genetics 26:19-20]. During the study, we encountered two unrelated girls, aged 17 and 11 years, who had clinical manifestations of the disorder, such as marfanoid habitus, waddling gait, muscular weakness, intense leg pain, flexion contracture of the hip and knee joints, delayed sexual development, increased serum alkaline phosphatase levels, and increased erythrocyte sedimentation rates. Radiographic studies in the two girls demonstrated not only diaphyseal dysplasia (cortical thickening of the diaphyses) resembling that of progressive diaphyseal dysplasia but also metaphyseal expansion of the long bones, coarse and thick trabeculae of the long and short tubular bones, striations in the spinal, pelvic, and long bones, and cranial sclerosis restricted to the petromastoid regions. These radiographic changes were overall identical with those seen in hyperostosis generalisata with striations of the bones rather than those in progressive diaphyseal dysplasia. Polymerase chain reaction-direct sequencing of all exons and their flanking regions of TGFB1 did not detect any mutations. PCR-single strand conformational polymorphism analysis of the TGF-beta type 1 receptor gene (TGFBR1) did not demonstrate any aberrant DNA fragments. We concluded from these findings that the two girls we described belong to a unique entity distinct from either of the two disorders.
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http://dx.doi.org/10.1002/ajmg.10079DOI Listing
January 2002