Aicardi-Goutières Syndrome Type 1: A Novel Missense Variant and Review of the Mutational Spectrum.

Objectives: Mutations in the TREX1 gene cause Aicardi-Goutières syndrome (AGS) 1, associated with a spectrum of autoimmune and neurodegenerative manifestations. AGS 1, the most severe neonatal type of AGS, is characterized by abnormal neurologic findings, visual inattention, hepatosplenomegaly, thrombocytopenia, skin rash, restlessness, and fever. Materials & Methods: The present study described two affected siblings from an Iranian family whose phenotypes overlap with intrauterine infections. They had almost similar presentations, including developmental delay, microcephaly, no fix and follow epileptic seizures and the same pattern of brain CT scan involvements. Following clinical and paraclinical assessments, whole-exome sequencing was employed to determine the disease-causing variant, and subsequently, PCR-Sanger sequencing was performed to indicate the segregation pattern of the candidate variant in family members. Results: Genetic analysis revealed a novel homozygous missense variant (c.461A>C; p.D154A) in the TREX1 gene in affected family members. Sanger sequencing of other family members showed the expected zygosities. Conclusion: This study identifies a novel mutation in the TREX1 gene in this family and highlights the efficiency of next-generation sequencing-based techniques for obtaining a definite diagnosis in patients with early-onset encephalopathy.

Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.

BACKGROUND: NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance. METHODS AND RESULTS: Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center. CONCLUSION: The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum.

BACKGROUND: Spinal muscular atrophy (SMA) could be classified as 5q and non-5q, based on the chromosomal location of causative genes. A rare form of non-5q SMA is an autosomal-recessive condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by myoclonic and generalized seizures with progressive neurological deterioration. SMA-PME is a clinically heterogeneous disorder that arises from biallelic pathogenic variants in ASAH1 gene. METHODS: Following clinical and primary laboratory assessments, whole-exome sequencing was performed to detect the disease-causing variants in three cases of SMA-PME from different families. Also, Multiplex ligation-dependent probe amplification (MLPA) was employed for determining the copy numbers of SMN1 and SMN2 genes to rule out 5q SMA. RESULTS: Exome sequencing revealed two different homozygous missense mutations (c.109 C > A [p.Pro37Thr] or c.125 C > T [p.Thr42Met]) in exon 2 of the ASAH1 gene in the affected members of the families. Sanger sequencing of the other family members showed the expected heterozygous carriers. In addition, no clinically relevant variant was identified in patients by MLPA. CONCLUSION: This study describes two different ASAH1 mutations and the clinical picture of 3 SMA-PME patients. In addition, previously reported mutations have been reviewed. This study could help to fortify the database of this rare disease with more clinical and genomic data.

Long Non-coding RNAs as Regulators of the Mitogen-activated Protein Kinase (MAPK) Pathway in Cancer.

BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway contributes to regulation of many cellular functions, such as cell proliferation and differentiation, mobility and apoptosis. Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) /p38 and ERK5 construct the three main modules in this pathway. The Raf-ERK1/2 and JNK cascades contribute in cell proliferation, migration, and survival and are principal regulators of malignant phenotype. This pathway is itself regulated by several outside signals as well as lateral signals from other pathways, which construct a complex network. Long non-coding RNAs (lncRNAs) as principal modulators of gene expression at transcriptional and post-transcriptional levels also regulate this pathway. In addition, lncRNA signature can be used as biomarker and target of novel treatment strategies in cancer patients. AIM: To explore the role of lncRNAs in regulation of MAPK pathway. CONCLUSION: Considering the role of this pathway in the pathogenesis of several cancers, alterations in lncRNA expression lead to changes in MAPK pathway resulting in inhibition of apoptosis and induction of cell proliferation and migration. Moreover, some lncRNAs participate in cross-talk between MAPK and other cancer-related pathways, such as PI3K/Akt pathway through regulation of certain shared proteins between these pathways. Based on the availability of certain anticancer drugs that modulate this pathway, identification of lncRNAs that affect this pathway would help in establishment of effective therapies.Key words: RNA - long noncoding - mitogen-activated protein kinases - signal transduction.

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.

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

Ovarian cancer is the most fatal tumor of female's reproductive system, and several genetics and environmental factors are involved in its development. Various studies have already identified some suitable biomarkers to facilitate the early detection, the prognosis evaluation, and the assessment of treatment response. However, the aim of this review is to investigate the role of long non-coding RNAs (lncRNAs) in tumorigenesis process of ovarian cancer and their potential applications as ovarian cancer biomarkers. We performed an online literature search of the MEDLINE/PubMed databases using the keywords, including ovarian cancer, lncRNA, and biomarker. We found that several lncRNAs have been shown to be deregulated in ovarian cancer and the specific mechanism of their enrollment in ovarian cancer has been defined for a few of them. In addition, expression profiling has revealed an association between lncRNAs and patients' survival, metastasis potential, as well as treatment response. Expression profiling and methylation analysis of lncRNAs in ovarian cancer may lead to the identification of novel biomarkers that can help in the classification of patients based on prognosis and treatment response.

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.