Copy number analysis from whole-exome sequencing data revealed a novel homozygous deletion in PARK7 leads to severe early-onset Parkinson's disease.

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.

Whole-Exome Sequencing Study of Consanguineous Parkinson's Disease Families and Related Phenotypes: Report of Twelve Novel Variants.

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.

Exosomal Long Noncoding RNAs: Insights into Emerging Diagnostic and Therapeutic Applications in Lung Cancer.

Lung cancer is the most common cause of cancer-related deaths worldwide. Annually, millions of people die from lung cancer because of late detection and ineffective therapies. Recently, exosomes have been introduced as new therapeutic players with the potential to improve upon current diagnostic and treatment options. Exosomes are small membranous vesicles produced during endosomal merging. This allows for cell packaging of nucleic acids, proteins, and lipids and transfer to adjacent or distant cells. While exosomes are a part of normal intercellular signaling, they also allow malignant cells to transfer oncogenic material leading to tumor spread and metastasis. Exosomes are an interesting field of discovery for biomarkers and therapeutic targets. Among exosomal materials, lncRNAs have priority; lncRNAs are a class of noncoding RNAs longer than 200 base pairs. In the case of cancer, primary interest regards their oncogene and tumor suppressor functions. In this review, the advantages of exosomal lncRNAs as biomarkers and therapeutic targets will be discussed in addition to reviewing studies of their application in lung cancer.

Role of long non-coding RNAs (LncRNAs) in multiple sclerosis: a brief review.

Multiple sclerosis (MS) as chronic autoimmune inflammatory neurological disease of the central nervous system (CNS) occurs due to several environmental and genetic factors, whose pathogenesis is associated with genes with regulatory role in the immune system. Long non-coding RNAs (LncRNAs) are able to reportedly regulate responses of immune systems and expression of genes, and show the tissue specificity and complexity of biofunctions. Various studies have suggested that the aberrant LncRNA expression is an underlying factor involved in the incidence of MS and that the analysis of the expression profile of these molecules can be a specific biomarker of MS for preventing the course of the disease or responding to treatment. The purpose of this research was to review the recent studies for exploring the functions of LncRNAs in the processes leading to MS disease.

Circulating Exosomes and Their Role in Stroke.

Stroke is an acute neurologic disorder which can be life-threatening if left untreated or diagnosed late. Various detecting techniques including neurologic imaging of the brain by computed tomography or magnetic resonance imaging can facilitate diagnosis of stroke. However, according to the recent advances in molecular detection techniques, new diagnostic and prognostic markers have emerged. Exosomes as an extra cellar particle are one of these markers which can have useful diagnostic, prognostic, and even therapeutic impact after stroke. We have previously discussed the role of exosomes in cardiovascular disease and in the present review we focus on the most common cerebrovascular disease. The aim of the present review is summarizing the recent diagnostic role of exosomes which are specifically secreted during a stroke and can guide clinicians to better diagnosis of stroke.

Down-regulation of RORA gene expression in the blood of multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and loss of oligodendrocytes. The demyelination process is caused by various subsets of CD4+ T cells with a Th1 and Th17 phenotype. The retinoid acid-related orphan receptor A (RORA) is expressed in Th17 cells and promote Th17 differentiation. In this study, we compared the expression level of RORA gene in the blood of 50 relapsing-remitting MS (RRMS) patients who were treated with IFN-ß and 50 healthy controls by TaqMan Quantitative Real-Time PCR.We found that RORA expression was significantly down-regulated in MS patients compared with controls (P= 0.006). However, there was no significant correlation between RORA gene expression and Kurtzke Expanded Disability Status Scale (EDSS). Our findings suggest a possible contribution of IFN-ß in the downregulation of RORA. In addition, RORA downregulation may be a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients.

Expression Analysis of Long Non-coding RNAs in the Blood of Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) with multiple genetic and environmental risk factors. Long non-coding RNAs (lncRNAs) have been recently reported to participate in the regulation of immune responses. Consequently, aberrant expression of lncRNAs has been suggested as an underlying cause of MS. In the present study, we evaluated the expression of three lncRNAs with putative roles in the regulation of immune response, namely TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL), Fas cell surface death receptor- antisense 1 (FAS-AS1), and plasmacytoma variant translocation 1 (PVT1) in circulating blood cells of 50 Iranian relapsing-remitting multiple sclerosis (RRMS) patients compared with healthy subjects by means of quantitative real-time polymerase chain reaction (PCR). We detected a significant downregulation of PVT1 and FAS-AS1 expressions in RRMS patients while a significant upregulation of THRIL in patients compared with controls (P < 0.001). Correlation analyses between lncRNA expression levels and clinical data of MS patients revealed no significant correlation between lncRNAs expression levels and Expanded Disability Status Scale (EDSS), a moderate correlation between PVT1 expression levels and duration of the disorder and no significant correlation between lncRNAs expression levels and age at onset. In addition, we demonstrated correlations between the expression levels of PVT1 and THRIL as well as expression levels of THRIL and FAS-AS1 in RRMS patients. In brief, we have demonstrated dysregulation of three lncRNAs in MS patients. Further studies are needed to explore the exact mechanisms by which these lncRNAs participate in regulation of immune responses.

Expression analysis of long non-coding ATB and its putative target in breast cancer.

BACKGROUND: A long noncoding RNA (lncRNA) activated by transforming growth factor (TGF)-ß (lncRNA-ATB) has been recently shown to promote the invasion-metastasis cascade in various types of cancers via upregulation of some targets including ZEB1. OBJECTIVES: The aim of the present study was to elucidate the expression of lncRNA-ATB and ZEB in breast cancer patients. METHODS: The expression of these genes was evaluated by real-time reverse transcription polymerase chain reaction in tumor samples form 50 newly diagnosed breast cancer patients as well as their corresponding adjacent non-cancerous tissues (ANCTs). Patients were divided into subsequent groups according to the median lncRNA-ATB expression. RESULTS: LncRNA-ATB has been shown to be downregulated in about two third of tumor samples compared with their ANCTs.A significant association has been found between ZEB1 expression and Ki-67 status. In addition, we demonstrated a correlation between expression of lncRNA-ATB and ZEB1 in tumor samples and not in ANCTs. CONCLUSION: Collectively, out data show downregulation of lncRNA-ATB in a significant number of breast tumor tissues compared with ANCTs and imply that lncRNA-ATB might have distinct roles in the pathogenesis of different cancers or even different subtypes of a certain cancer which should be evaluated in future studies.

Expression Study and Clinical Correlations of MYC and CCAT2 in Breast Cancer Patients

Background: Colon cancer-associated transcript 2 (CCAT2) is a newly recognized lncRNA transcribed from the 8q24 genomic region. It functions as an oncogene in various types of cancers including breast cancer, in which it affects Wnt/ß-catenin pathway. Previous studies have shown a putative interaction between this lncRNA and MYC proto-oncogene. Methods: In the current study, we evaluated the expression of CCAT2 in breast cancer tissues with regards to the expression of its target MYC. In addition, we assessed the relationship between CCAT2 and MYC expression levels in tumor tissues and the clinical prognostic characteristics of breast cancer patients. Results: MYC expression levels were significantly up-regulated in tumor tissues compared with adjacent non-cancerous tissues (ANCTs), while such analysis showed no statistically significant difference between these two tissue types in CCAT2 expression. Starkly increased CCAT2 gene expression levels were found in 12/48 (25%) of cancer tissue samples compared with their corresponding ANCTs. Furthermore, significant inverse correlations were found between CCAT2 expression and stage, as well as lymph node involvement. Besides, a significant inverse correlation was found between the relative MYC expression in tumor tissues compared with their corresponding ANCTs and disease stage. Conclusion: These results highlight the significance of MYC and CCAT2 expressions in the early stages of breast cancer development and suggest a potentially significant role for CCAT2 in a subset of breast cancer patients, which could be applied as a potential therapeutic target in these patients.

Comparative expression analysis of hypoxia-inducible factor-alpha and its natural occurring antisense in breast cancer tissues and adjacent noncancerous tissues.

Hypoxia-inducible factors (HIFs) have been shown to be upregulated in tumor tissues and linked with tumor progression and metastasis in breast cancer. Among regulatory mechanisms for HIF expression is a natural occurring antisense named aHIF, which has been shown to be overexpressed in breast cancer and influence the level of the HIF-1α transcript. In the present study, we analyzed the expression of HIF-1α and aHIF in breast cancer tissues versus adjacent noncancer tissues (ANCTs) in relation with the clinical and biological behavior of the tumors. aHIF has been shown to be expressed in 67.4% of invasive ductal carcinoma samples, while none of ANCTs showed its expression. HIF-1α has been expressed in all of tumors and 90% of ANCTs. Comparison of HIF-1α expression level between tumor and ANCT tissues showed a total upregulation in tumor samples. No statistically significant association has been found between the level of HIF-1α expression in tumor samples and clinicopathologic and demographic characteristics such as age, tumor size, estrogen receptor status, progesterone receptor status, HER2/neu expression level, lymph node status, histological grade, and stage except for a weak correlation between HIF-1α expression and Ki-67 status. Besides, we could not detect any significant correlation between relative expression of HIF-1α and aHIF in tumor samples. Collectively, these data suggest that aHIF overexpression can be used as a potential biomarker in breast cancer. However, further studies are needed for the evaluation of its mechanism of action in regulation of HIF-1α expression in different pathological conditions. HIF-1α overexpression results in the upregulation of several genes that participated in cancer-associated pathways such as proliferation, angiogenesis, and glucose metabolism. We showed that HIF-1α is upregulated in breast tumor samples compared with adjacent noncancerous tissues. Its expression has been associated with Ki-67 status. Its natural occurring antisense is only expressed in tumor tissues. Thus, it can be used as a potential biomarker in breast cancer.

The Role of Long Non-Coding RNAs in Breast Cancer.

Long non-coding RNA (lncRNA) genes are an important population of non-coding RNAs with defined key roles in normal development as well as tumorigenesis process. Evidences suggest that they can be classified as tumor suppressor genes or oncogenes according to their functions and expression pattern in tumoral tissues. They have been shown to regulate the plasticity of cancer stem cells. Their important roles in the regulation of cancer-related pathways in addition to deregulation of their expression in a number of cancers have suggested that they can be used as markers for cancer detection and prognosis, as well as targets for cancer treatment. Deregulation of a number of lncRNAs, such as HOTAIR, XIST, MALAT, and H19 has been detected in breast cancer samples and cell lines. In addition, the association between lncRNAs signature and breast cancer patients' survival has been assessed in various studies. Here, the expression patterns of lncRNAs in breast cancer, as well as their significance in prognosis and patient treatment are discussed.

Expression analysis of four long noncoding RNAs in breast cancer.

Breast cancer is a molecularly heterogeneous disease which necessitates a search for markers to provide a more specific classification of this disorder. Long noncoding RNAs as the important subset of noncoding transcripts have been shown to be involved in tumorigenic processes. So, they may be used as markers for early detection of cancer and evaluation of cancer prognosis. In addition, they can be applied as therapeutic targets. In this study, we analyzed expression of four long noncoding RNAs (lncRNAs) namely SOX2OT, PTPRG-AS1, ANRASSF1, and ANRIL in 38 breast cancer tissues and their adjacent noncancerous tissues (ANCTs). ANRASSF1 expression was not detected in any noncancerous tissue. All lncRNAs showed significant overexpression in tumor tissues compared with ANCTs. No association was found between gene expressions and individual clinical data such as tumor stage, grade, size and hormone receptor status except for ANRASSF1 expression and Her2/neu status. In addition, ANRASSF1 and ANRIL expressions were significantly higher in triple negative samples. This study suggests a putative role for these lncRNAs in breast cancer and implies that they can be used as potential cancer biomarkers.