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BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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Distonia , Distúrbios Distônicos , Doença de Parkinson , Algoritmos , Distonia/diagnóstico , Distonia/genética , Distúrbios Distônicos/genética , Testes Genéticos , HumanosRESUMO
Venous and arterial thrombosis are conditions that have a considerable burden if left untreated. The hypoxia-induced by the occluded vessel can disrupt the circulation of any organ, the cornerstone of treating thrombosis is rapid diagnosis and appropriate treatment. Diagnosis of thrombosis may be made by using laboratory tests or imaging techniques in individuals who have clinical manifestations of a thrombotic event. The use of serum micro ribonucleic acids (RNAs) has recently been applied to the diagnosis of thrombosis. These small RNA molecules are emerging as new diagnostic markers but have had very limited applications in vascular disease. Most of the articles provided various microRNAs with different levels of accuracy. However, there remains a lack of an appropriate panel of the most specific microRNA in the literature. The purpose of the present review was to summarize the existing data on the use of microRNAs as a diagnostic biomarker for venous thrombosis.
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Biomarcadores/sangue , MicroRNAs/sangue , Trombose Venosa/sangue , Trombose Venosa/diagnóstico , HumanosRESUMO
Stroke is one of the most common type of cerebrovascular disease threatening human health and life with high mortality, disability, and morbidity. Ischemic stroke (IS) is determined to be a complex disease containing a group of heterogeneous disorders with various environmental and genetic risk factors. This study evaluated the polymorphisms of microRNAs involved in inflammatory routes leading to stroke in an Iranian population. This study evaluated the associations of hsa-mir-608 C/G rs4919510, hsa-mir-499 A/G rs3746444, and hsa-mir-145 C/T rs190323149 polymorphisms in precursor miRNAs with the risk of IS. These microRNA polymorphisms were analyzed in 470 patients with IS and 489 control subjects. The TOAST criteria was applied for IS subtypes classification. The frequency of the allele G of hsa-mir-499/rs3746444 A/G revealed significant association with IS in comparison with controls ( p < 0.0001, OR = 1.838, 95% CI = 1.406-2.401). Increased IS risks were associated with hsa-mir-499/ rs3746444 A/G genotypes in diverse genetic model (homozygote comparison: p = 0.004, OR = 2.136, 95% CI = 1.269-3.597; heterozygote comparison: p = 0.029, OR = 1.373, 95% CI = 1.033-1.825). Statistical analysis in IS subtypes showed that cardio-embolic patients compared with other subtypes (large artery atherosclerosis and lacunar) had higher frequency of G allele (LAA vs. CEI, p = 0.017; LAC vs. CEI, p = 0.009), AG genotype (LAA vs. CEI, p = 0.016; LAC vs. CEI, p = 0.013). Nevertheless, this study did not find any association between the alleles and genotypes of mir-608 C/G rs4919510 SNP and IS, respectively ( p > 0.05). The current investigation provided verification that hsa-mir-499 rs3746444 A/G polymorphism may be associated with a significantly increased risk of IS in an Iranian population.
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Isquemia Encefálica/genética , Inflamação/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Inflamação/diagnóstico , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnósticoRESUMO
Coronary artery disease (CAD) and ischemic stroke (IS) are commonly considered distinct disease phenotypes. However, there is some evidence in favor of a degree of overlap between genetic susceptibility to CAD and genetic risk factors for IS. In the present study, we aimed to examine the role of two single-nucleotide polymorphisms (SNPs), rs3825807 and rs11556924, located in the ADAMTS7 and ZC3HC1 genes, respectively, associated with CAD in published GWASs in European populations and their possible contribution to the development of coronary atherosclerosis and cerebral LA atherosclerosis in a case-control study of an the Iranian population. The sample size was 400, and the methodology for SNP genotyping was ARMS-PCR. Both SNPs showed strong associations with CAD in the analyses comparing significant CAD and myocardial infarction (MI) with controls. None of them, however, were associated with MI in patients with significant CAD. Our findings further support the role of the ADAMTS7 locus in promoting atherosclerosis in LAs of the brain. Regarding ZC3HC1 rs11556924, our study further supports the observed association of rs11556924 with LA IS coming from previous GWASs. In conclusion, the data showed that common variants in ADAMTS7 and ZC3HC1 genes contribute to an increased risk for both CAD and LA (atherosclerotic) IS.
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Proteína ADAMTS7/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Adulto , Idoso , Alelos , Aterosclerose/complicações , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Irã (Geográfico) , Ataque Isquêmico Transitório/complicações , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicaçõesRESUMO
PURPOSE: APOBEC3B belongs to the family of DNA-editing enzymes. A copy number variant targeting the genomic APOBEC3A-APOBEC3B locus has a significant impact on breast cancer risk, but the relative contribution of APOBEC3B is uncertain. In this study, we investigate a loss-of-function mutation that selectively targets APOBEC3B, for its association with breast cancer risk. METHODS: We performed exome sequencing on genomic DNA samples of 6 Byelorussian patients with familial breast cancer. We then studied through mutation-specific genotyping four hospital-based breast cancer case-control series from Belarus, Russia, Germany, and Iran, respectively, comprising a total of 3070 breast cancer patients and 2878 healthy females. Results were evaluated using fixed-effects meta-analyses. RESULTS: Exome sequencing uncovered a frameshift mutation, APOBEC3B*c.783delG, that was recurrent in the study populations. Subsequent genotyping identified this mutation in 23 additional breast cancer cases and 9 healthy female controls, with an adjusted Odds Ratio 2.29 (95% CI 1.04; 5.03, P = 0.04) in the combined analysis. There was an enrichment of the c.783delG mutation in patients with breast cancer diagnosed below 50 years of age (OR 3.22, 95% CI 1.37; 7.56, P = 0.007). CONCLUSIONS: APOBEC3B*c.783delG showed evidence of modest association with breast cancer and seemed to contribute to earlier onset of the disease. These results may need to be reconciled with proposals to consider APOBEC3B as a possible therapeutic target in breast cancer.
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Alelos , Neoplasias da Mama/genética , Citidina Desaminase/genética , Antígenos de Histocompatibilidade Menor/genética , Deleção de Sequência , Adulto , Idade de Início , Idoso , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Efeito Fundador , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Sequenciamento do ExomaRESUMO
Diabetes in pregnancy impairs hippocampus development in offspring, leading to behavioral problems and learning deficits. Phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt) signaling pathway plays a pivotal role in the regulation of neuronal proliferation, survival and death. The present study was designed to examine the effects of maternal diabetes on PKB/Akt expression and phosphorylation in the developing rat hippocampus. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at first postnatal day (P1). The hippocampal expression and phosphorylation level of PKB/Akt, one of the key molecules in PI3K/AKT signaling pathway, was evaluated using real-time polymerase chain reaction (PCR) and western blot analysis. We found a significant bilateral downregulation of AKT1 gene expression in the hippocampus of pups born to diabetic mothers (p < 0.05). Interestingly, our results revealed a marked upregulation of Akt1 gene in insulin-treated group compared with other groups (p < 0.05). The western blot analysis also showed the reduction of phosphorylation level of all AKT isoforms in both diabetic and insulin-treated groups compared with control (p < 0.05). Moreover, the results showed a significant increase in phosphorylation level of AKT in insulin-treated group compared with the diabetic group. These results represent that diabetes during pregnancy strongly influences the regulation of PKB/AKT in the developing rat hippocampus. Furthermore, although the control of glycemia by insulin administration is not sufficient to prevent the alterations in PKB/Akt expression, it modulates the phosphorylation process, thus ultimately resulting in a situation comparable to that found in the normal condition.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hipocampo/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Western Blotting , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Insulina/farmacologia , Insulina/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , EstreptozocinaRESUMO
In Iran and the rest of the world, breast cancer (BC) is the most common malignancy in women. Familial history and age are significant risk factors for the development of this disease in Iran. Most hereditary BCs are associated with inherited mutations in the BRCA1 and BRCA2 genes. Some recent studies demonstrated that BRCA1 mutations are seen in high-risk women with family histories of BC. In this report we investigated all BRCA1 exons from 40 female patients with family histories of BC and one BC twin, and report a novel mutation in this gene in one patient. As controls, BRCA1 exons from 100 normal women and the BC-free twin of the BC twin were also examined for this mutation. None of the women in the normal group harbored the mutation. Whether this variation is specific for the Iranian population or for special subgroups remains to be determined.
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Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Adulto , Estudos de Casos e Controles , DNA/análise , DNA/genética , Família , Feminino , Humanos , Irã (Geográfico) , Linhagem , Reação em Cadeia da Polimerase , Fatores de Risco , Adulto JovemRESUMO
Parkinson's disease (PD), a neurodegenerative disease characterized by both motor neuron and non-motor neuron symptoms, is the most frequent neurodegenerative disease after Alzheimer's disease. Both genetic and environmental factors take part in disease etiology. Most cases are considered complex multifactorial diseases. About 15% of PD appear in the familial form, and about 5% of all cases arise from a single gene mutation. Among Mendelian causes of PD, PARK7 is one of the autosomal recessive forms due to loss-of-function mutations in both gene alleles. Both single nucleotide variants (SNVs) and copy number variations (CNVs) are observed in PARK7. This study presents an Iranian family with familial PD where some relatives had psychiatric disorders. A homozygous 1617 bp deletion in a female with early-onset PD was detected through copy-number analysis from whole-exome sequencing (WES) data in this consanguineous family. Further investigation by surveying microhomology revealed that the actual size of the deletion is 3,625 bp. This novel CNV that was in the PARK7gene is supposed to co-relation with early-onset PD and infertility in this family.
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Relative internet search volumes (RSV) is now being consider as a measurement of awareness for most of the trending topics. During the recent coronavirus disease (COVID-19) outbreak, many researchers used the RSVs to interpret the population responses to the pandemic in various ways. By using the RSVs searched by Persian language people, we demonstrated that the Iranian people increased their knowledge and awareness of COVID-19 during the early phases of the disease before the first peak. However, their relative searches about the COVID-19 and its clinical symptoms decreased gradually despite of the gradual rise of the confirmed cases. Their less tendency to seek information about the COVID-19 could be one of the possible explanation for the increasing number of confirmed cases even several days after easing the disease related lockdown.
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BACKGROUND: Cerebral palsy (CP) is a permanent neurodevelopmental disorder with considerable global disability. Various rehabilitation strategies are currently available. However, none represents a convincing curative result. Cellular therapy recently holds much promise as an alternative strategy to repair neurologic defects. METHOD: In this narrative review, a comprehensive search of the MEDLINE and ClinicalTrials.gov was made, using the terms: "cell therapy" and "cerebral palsy", including published and registered clinical studies, respectively. RESULTS: The early effects of these studies demonstrated that using cell therapy in CP patients is safe and improves the deficits for a variable duration. Despite such hopeful early bird results, the long-term outcomes are not conclusive. CONCLUSIONS: Due to the heterogeneous nature of CP, personal factors seem essential to consider. Cell dosage, routes of administration, and repeated dosing are pivotal to establish optimal personalized treatments. Future clinical trials should consider employing other cell types, specific cell modifications before administration, and cell-free platforms.
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Paralisia Cerebral , Paralisia Cerebral/reabilitação , Humanos , ParalisiaRESUMO
Familial Mediterranean fever (FMF) typically presents with recurrent attacks of fever and serosal inflammation with peritoneum, pleura, and synovium. We usually do not expect pericardial involvement at the early stages. FMF is an autoinflammatory disease, usually inherited with an autosomal recessive pattern. The patients typically have biallelic mutations in the MEFV gene, located on chromosome 16. Colchicine is the first-line treatment of FMF, which not only plays a crucial prophylactic role regarding the attack episodes, but also prevents amyloidosis. Colchicine resistance and intolerance in FMF patients have been rarely reported. Alternative anti-inflammatory agents are understood to be helpful in such cases. We describe a 13-year-old boy referred to our pediatric department complaining of chest pain, dyspnea, and tachycardia. Due to the massive pericardial and pleural effusion, a pericardiocentesis was performed, and a chest tube was inserted. Cardiac tamponade was considered as the initial diagnosis. After a month, he faced another episode of pleuritic chest pain, fever, tachycardia, and pleural and pericardial effusion. Evaluation for probable differential diagnoses including infection, malignancy, and collagen vascular disease showed no remarkable results. Finally, the mutation found by whole exome sequencing was confirmed by direct Sanger sequencing revealing a heterozygote c.44G > C (p.Glu148Gln) mutation in exon 2, confirming the clinical diagnosis of familial Mediterranean fever. Since he seemed to be nonresponsive to the maximum standard dose of colchicine, 100 mg of daily dapsone was added to his treatment regimen, which controlled the attack episodes well. FMF, while rarely initiated with cardiac manifestation, should be considered in patients with any early signs and symptoms of cardiovascular involvement.
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Breast cancer is the most frequent malignancy among women in both developed and developing countries. Although several genes have been identified to harbor germline variants contributing to breast cancer risk, much of the heritability for breast cancer is yet undefined. In the present study, we have performed exome sequencing to detect susceptibility genes in an Iranian family with five first-degree family members affected with breast cancer. We identified novel candidate variants with predicted pathogenicity in RASSF1, KLK3 and FAM81B. The RASSF1 and KLK3 variants, but not the FAM81B variant, partially co-segregated with disease in the investigated pedigree and were not found in additional screenings outside the specific family. RASSF1 p.S135F is a missense substitution abolishing the ATM phosphorylation site, and KLK3 variant p.M1? is a deletion at the initiation codon that is predicted to abolish translation to the functional kallikrein protease, PSA. Our study suggests germline variation in RASSF1 and KLK3 as potential candidate contributors to familial breast cancer predisposition and illustrates the difficulties to determine the causal genetic risk factor among novel variants restricted to a single family.
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Neoplasias da Mama , Exoma , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Células Germinativas , Humanos , Irã (Geográfico) , Calicreínas , Linhagem , Antígeno Prostático Específico , Proteínas Supressoras de Tumor/genéticaRESUMO
Parkinson's disease (PD) is a common progressive neurodegenerative disorder with motor and nonmotor symptoms. Recent studies demonstrate various susceptibility loci and candidate genes for familial forms of the disease. However, the genetic basis of the familial form of early-onset PD (EOPD) is not widely studied in the Iranian population. Therefore, the present study aimed to investigate the possible causative genetic variants responsible for developing EOPD among Iranian patients. Iranian patients with a clinical diagnosis of Parkinson's disease were evaluated, and 12 consanguineous families with at least two affected individuals with early-onset PD (EOPD) were chosen to enroll in the present study. An expert neurologist group examined these families. Whole-exome sequencing (WES) was performed on PD patients, and the possible causative genetic variants related to the development of PD were reported. Exome sequencing (WES) was performed on every PD patient and revealed that patients had novel genetic variants in PRKN, PARK7, and PINK1 genes. All the genetic variants were in homozygous status and none of these variants were previously reported in the literature. Moreover, these genetic variants were "pathogenic" based on bioinformatic studies and according to the American College of Medical Genetics (ACMG). The present research revealed some novel variants for EOPD among the Iranian population. Further functional studies are warranted to confirm the pathogenicity of these novel variants and establish their clinical application for the early diagnosis of EOPD.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Sequenciamento do Exoma , Irã (Geográfico) , Mutação , Fenótipo , Idade de InícioRESUMO
INTRODUCTION: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565). METHODS: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. RESULTS: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). CONCLUSIONS: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches.
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Aminopeptidases/genética , Distonia , Distúrbios Distônicos , Transtornos Parkinsonianos , Criança , Distonia/genética , Distúrbios Distônicos/genética , Humanos , Irã (Geográfico) , Mutação , LinhagemRESUMO
OBJECTIVES: Dermatopontin (DPT) is an extracellular matrix protein that plays roles in increasing the activity of transforming growth factor-ß (TGF-ß) 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%, P=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-ß expression in colorectal cancer demonstrate that DPT may act as a pre-receptor component of the TGF-ß signaling pathway in colon carcinogenesis.
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N-methyl-d-aspartate receptors (NMDARs) are expressed abundantly in the brain and play a crucial role in the regulation of central nervous system (CNS) development, learning, and memory. During early neuronal development, NMDARs modulate neurogenesis, neuronal differentiation and migration, and synaptogenesis. The present study aimed to examine the developmental expression of NMDARs subunits, NR1 and NR2B, in the developing hippocampus of neonatal rats during the first two postnatal weeks. Fifty-four male offspring were randomly divided into three age groups, postnatal days (P) 0, 7, and 14. Real-time-PCR, western blotting, and immunohistochemistry (IHC) analyses were employed to examine and compare the hippocampal expression of the NMDA receptor subunits. The highest mRNA expression of NR1 and NR2B subunits was observed at P7, regardless of its laterality. The mRNA expression of both subunits in the right hippocampus was significantly higher than that of the left one at P0 and P7. Similarly, the highest protein level expression of NR1 and NR2B subunits was also observed at P7 in both sides hippocampi. Although the protein expression of NR1 was significantly higher on the right side in all studied days, the NR2B was significantly higher in the right hippocampus only at P7. The analysis of optical density (OD) has shown a marked increase in the distribution pattern of the NR1 and NR2B subunits at P7 in all hippocampal subregions. In conclusion, there is a marked right-left asymmetry in the expression of NR1 and NR2B subunits in the developing rat hippocampus, which might be considered as a probable mechanism for the lateral differences in the structure and function of the hippocampus in rats.
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Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Masculino , Ratos , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
OBJECTIVES: Infantile neuroaxonal degeneration (INAD) is a rare subgroup of neurodegeneration with brain iron accumulation (NBIA) disorders. This progressive disorder may develop during the early years of life. Affected individuals mostly manifest developmental delay and/or psychomotor regression as well as other neurological deficits. In the present study, we discussed 3 INAD patients diagnosed before the age of 10 by using Whole-Exome Sequencing (WES). MATERIALS AND METHODS: We evaluated 3 pediatric patients with clinical phenotypes of INAD who underwent WES. Sanger sequencing was performed for co-segregation analysis of the variants in the families. An in-silico study was conducted for identification of the molecular function of the identified genetic variants in the PLA2G6 gene. RESULTS: We detected three novel genetic variants in the PLA2G6 gene including a homozygous missense (NM_003560.2; c.1949T>C; p.Phe650Ser), a splicing (NM_001349864; c.1266-1G>A) and a frameshift variant (NM_003560.4; c.1547_1548dupCG; p.Gly517ArgfsTer29). Since the variants were not previously reported in literature or population databases, we performed in-silico studies for these variants and demonstrated their potential pathogenicity. CONCLUSION: The current study reports novel genetic variants in the PLA2G6 gene in the Iranian population, emphasizing the importance of high-throughput genetic testing in rare diseases.
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INTRODUCTION: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. METHODS: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. RESULTS: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. CONCLUSIONS: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
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Variações do Número de Cópias de DNA , Distonia/genética , Distúrbios Distônicos/genética , Sequenciamento do Exoma , Adulto , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Distonia/diagnóstico , Distúrbios Distônicos/diagnóstico , Feminino , Humanos , MasculinoRESUMO
The purpose of this study was to describe the distinct regional distribution patterns of expression of the α7 and α4 subunits of nicotinic acetylcholine receptors (nAChRs) and their left-right lateralisation in the rat hippocampus during the first 2 weeks of postnatal (P) development. Eighteen male pups were randomly divided into three groups: P0, P7, and P14. After removing the newborn brains, real-time polymerase chain reaction, western blot, and immunohistochemistry techniques were used to evaluate expression of the receptors. Results indicated that the expression profile of these receptors were time- and spatially dependent. A significant increase was observed in the distribution of α7 and α4 nAChR subunits in the developing rat hippocampus from P0 to P7 (p < .001); however, there was a significant decrease from P7 to P14 (p < .05). As a spatial effect, the highest optical density (OD) was observed in the CA3 and CA2 regions of the hippocampus, while the lowest OD was in the dentate gyrus. Moreover, the distribution of α7 and α4 nAChR subunits in the left hippocampus was significantly higher than their counterparts in the right (p < .05). From these data, the expression patterns of α7 and α4 nAChR subunits exhibited left-right asymmetry in the developing rat hippocampus.
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Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Região CA2 Hipocampal/crescimento & desenvolvimento , Região CA2 Hipocampal/metabolismo , Região CA3 Hipocampal/crescimento & desenvolvimento , Região CA3 Hipocampal/metabolismo , DNA Complementar/biossíntese , Feminino , Lateralidade Funcional , Imuno-Histoquímica , Masculino , Gravidez , RNA/biossíntese , Ratos , Ratos Wistar , Receptores Nicotínicos/genética , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
Background Phenylketonuria (PKU) is a common metabolic disorder with great burden if left untreated or undiagnosed. Genetic variations in the phenylalanine hydroxylase (PAH) gene may be widely varied across different regions of a country. By knowing the most common mutations, diagnostic work-ups will be offered sooner and with lower costs for patients. The present study defines the most common genetic variations in the PAH gene in Khorasan province of Iran. Methods The present cross-sectional study took place in Khorasan province of Iran within a 6-year period starting from 2012 to 2018. Every patient who had been referred as suspicious PKU cases or referred for prenatal diagnosis was included in the present study. Results A total number of 122 individuals with a mean age of 26.22 years were enrolled in the present study. The most frequent genetic variations in the PAH gene were c.1066-11G > A and c.143 T > C. Exon 7 carried the most genetic variations compared to any single exon. Also, three patients had compound heterozygous status for c.727 C > T/c.1066-11 G > A in exon 7 and 11 of the PAH gene. Conclusions Mutations in the PAH gene are widely varied among different populations, and our results confirmed this fact. Determination of the most prevalent mutations and polymorphisms in each region will reduce the time and cost of diagnosing such preventable diseases and will therefore reduce the disease burden.