Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS).

Introduction: The CSF1R gene encodes the receptor for colony-stimulating factor-1, the macrophage, and monocyte-specific growth factor. Mutations in this gene cause hereditary diffuse leukoencephalopathy with spheroids (HDLS) with autosomal dominant inheritance and BANDDOS (Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis) with autosomal recessive inheritance. Methods: Targeted gene sequencing was performed on the genomic DNA samples of the deceased patient and a fetus along with ten healthy members of his family to identify the disease-causing mutation. Bioinformatics tools were used to study the mutation effect on protein function and structure. To predict the effect of the mutation on the protein, various bioinformatics tools were applied. Results: A novel homozygous variant was identified in the gene CSF1R, c.2498C>T; p.T833M in exon 19, in the index patient and the fetus. Furthermore, some family members were heterozygous for this variant, while they had not any symptoms of the disease. In silico analysis indicated this variant has a detrimental effect on CSF1R. It is conserved among humans and other similar species. The variant is located within the functionally essential PTK domain of the receptor. However, no structural damage was introduced by this substitution. Conclusion: In conclusion, regarding the inheritance pattern in the family and clinical manifestations in the index patient, we propose that the mentioned variant in the CSF1R gene may cause BANDDOS.

A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare disorder that affects both upper and lower motor neurons. Mutations in Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) correlates with three similar but distinctive syndromes, including the juvenile form of ALS. An Iranian Kurdish family was involved in this study and all members were evaluated with relevant clinical guidelines. Whole exome sequencing and sanger sequencing were applied to all family members to undermine the possible genetic factors. A substitution c. 2110 C>T (p. Arg704X) identified in the ALS2 gene. Bioinformatics analysis indicated the mutation is located in the well-conserved and functional domain of the protein. This study recognized a novel mutation in the ALS2 gene in a proband with the juvenile form of ALS. To our knowledge, this is the first identified ALS2 mutation among the Iranian population.

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer's Disease: A Systematic Scoping Review.

Alzheimer's disease (AD) is a heterogeneous degenerative brain disorder with a rising prevalence worldwide. The two hallmarks that characterize the AD pathophysiology are amyloid plaques, generated via aggregated amyloid ß, and neurofibrillary tangle, generated via accumulated phosphorylated tau. At the post-transcriptional and transcriptional levels, the regulatory functions of non-coding RNAs, in particular long non-coding RNAs (lncRNAs), have been ascertained in gene expressions. It is noteworthy that a number of lncRNAs feature a prevalent role in their potential of regulating gene expression through modulation of microRNAs via a process called the mechanism of competing endogenous RNA (ceRNA). Given the multifactorial nature of ceRNA interaction networks, they might be advantageous in complex disorders (e.g., AD) investigations at the therapeutic targets level. We carried out scoping review in this research to analyze validated loops of ceRNA in AD and focus on ceRNA axes associated with lncRNA. This scoping review was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was conducted to find eligible articles prior to July 2021. Two reviewers independently performed publications screening and data extraction, and quantitative and qualitative analyses were conducted. Fourteen articles were identified that fulfill the inclusion criteria. Studies with different designs reported nine lncRNAs that were experimentally validated to act as ceRNA in AD in human-related studies, including BACE1-AS, SNHG1, RPPH1, NEAT1, LINC00094, SOX21-AS1, LINC00507, MAGI2-AS3, and LINC01311. The BACE1-AS/BACE1 was the most frequent ceRNA pair. Among miRNAs, miR-107 played a key role by regulating three different loops. Understanding the various aspects of this regulatory mechanism can help elucidate the unknown etiology of AD and provide new molecular targets for use in therapeutic and clinical applications.

Long non-coding RNA-associated competing endogenous RNA axes in the olfactory epithelium in schizophrenia: a bioinformatics analysis.

The etiology of schizophrenia (SCZ), as a serious mental illness, is unknown. The significance of genetics in SCZ pathophysiology is yet unknown, and newly identified mechanisms involved in the regulation of gene transcription may be helpful in determining how these changes affect SCZ development and progression. In the current work, we used a bioinformatics approach to describe the role of long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) in the olfactory epithelium (OE) samples in order to better understand the molecular regulatory processes implicated in SCZ disorders in living individuals. The Gene Expression Omnibus database was used to obtain the OE microarray dataset (GSE73129) from SCZ sufferers and control subjects, which contained information about both lncRNAs and mRNAs. The limma package of R software was used to identify the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). RNA interaction pairs were discovered using the Human MicroRNA Disease Database, DIANA-LncBase, and miRTarBase databases. In this study, the Pearson correlation coefficient was utilized to find positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Eventually, lncRNA-associated ceRNA axes were developed based on co-expression relations and DElncRNA-miRNA-DEmRNA interactions. This work found six potential DElncRNA-miRNA-DEmRNA loops in SCZ pathogenesis, including, SNTG2-AS1/hsa-miR-7-5p/SLC7A5, FLG-AS1/hsa-miR-34a-5p/FOSL1, LINC00960/hsa-miR-34a-5p/FOSL1, AQP4-AS1/hsa-miR-335-5p/FMN2, SOX2-OT/hsa-miR-24-3p/NOS3, and CASC2/hsa-miR-24-3p/NOS3. According to the findings, ceRNAs in OE might be promising research targets for studying SCZ molecular mechanisms. This could be a great opportunity to examine different aspects of neurodevelopment that may have been hampered early in SCZ patients.

An updated overview and classification of bioinformatics tools for MicroRNA analysis, which one to choose?

The term 'MicroRNA' (miRNA) refers to a class of small endogenous non-coding RNAs (ncRNAs) regenerated from hairpin transcripts. Recent studies reveal miRNAs' regulatory involvement in essential biological processes through translational repression or mRNA degradation. Recently, there is a growing body of literature focusing on the importance of miRNAs and their functions. In this respect, several databases have been developed to manage the dispersed data produced. Therefore, it is necessary to know the parameters and characteristics of each database to benefit their data. Besides, selecting the correct database is of great importance to scientists who do not have enough experience in this field. A comprehensive classification along with an explanation of the information contained in each database leads to facilitating access to these resources. In this regard, we have classified relevant databases into several categories, including miRNA sequencing and annotation, validated/predicted miRNA targets, disease-related miRNA, SNP in miRNA sequence or target site, miRNA-related pathways, or gene ontology, and mRNA-miRNA interactions. Hence, this review introduces available miRNA databases and presents a convenient overview to inform researchers of different backgrounds to find suitable miRNA-related bioinformatics web tools and relevant information rapidly.

Mutational analysis of CYP1B1 gene in Iranian pedigrees with glaucoma reveals known and novel mutations.

PURPOSE: Primary congenital glaucoma (PCG) (OMIM#231,300) can be caused by pathogenic sequence variations in CYP1B1, LTBP2, MYOC and PXDN genes. The purpose of this study was to investigate mutations in the CYP1B1 gene in families affected with primary congenital glaucoma (PCG) using linkage analysis and Sanger sequencing. METHODS: A total number of four families with nine affected PCG patients during six months were included in this study. The mutations were identified by homozygosity mapping to find the linked loci and then direct sequencing of all coding exons, the exon-intron boundaries and the 5' untranslated region of CYP1B1 using genomic DNA obtained from affected family members and their parents. Moreover, bioinformatic tools were applied to study mutation effect on protein structure and function. RESULTS: A total of four mutations were identified, and three of these were novel. Two were missense mutations: One was truncating mutation, and the other was an in-frame deletion. Mutations in CYP1B1 could fully explain the PCG phenotype in all of the patients. Also, the bioinformatic study of the mutations showed the structure of the protein is affected, and it is well conserved among similar species. CONCLUSION: In this study, we identified 4 CYP1B1 mutations, 3 of which were novel. In silico analysis of identified mutations confirmed their molecular pathogenicity. A similar analysis will help understand the biological role of CYP1B1 and the effect of mutations on the regulatory and enzymatic functions of CYP1B1 that result in PCG. CLINICAL TRIALS REGISTRATION: Not relevant.

A novel splice site mutation in the SDCCAG8 gene in an Iranian family with Bardet-Biedl syndrome.

PURPOSE: Bardet-Biedl syndrome (BBS: OMIM 209,900) is a rare ciliopathic human genetic disorder that affects many parts of the body systems. BBS is a genetically heterogeneous disorder with a wide spectrum of clinical manifestations which makes its diagnosis and management more challenging. RetNet reports 18 genes that cause BBS and each of genes has had several known mutations. Genetic studies suggesting that serologically defined colon cancer antigen 8 (SDCCAG8) gene mutations are a major cause of BBS. MATERIALS AND METHODS: In this section, we investigated the consanguineous Iranian family members with BBS. Whole-exome sequencing and Sanger sequencing, were performed to screen and confirm the suspicious pathogenic mutations. The identified mutation was investigated using bioinformatics tools to predict the effect of the mutation on protein structure. RESULTS: Sequential analysis identified a novel splice site mutation c.1221 + 2 T > A in the SDCCAG8 gene in BBS patients. Structure-based approaches have predicted significant structural alterations in SDCCAG8 protein. CONCLUSIONS: This study was conducted to show the aberrant alternative splicing as one of the single splicing mutations identified can cause BBS by affecting the function of SDCCAG8 protein.

LRP8 (rs5177) and CEP85L (rs11756438) are contributed to schizophrenia susceptibility in Iranian population.

Introduction Schizophrenia is recognized as one of the most important mental illnesses of the last century. Many genetic and environmental factors are involved in this condition. Recently, the genome-wide association study identified two significant genes LRP8 and CEP85L associated with psychiatric disorders. LRP8 (low-density lipoprotein receptor-related protein 8) acts as a cytoplasmic receptor for Reelin. Many studies have revealed that LRP8 was significantly related to schizophrenia and bipolar disorder in Chinese population. CEP85L standing for 'centrosomal protein 85 kDa-like' is another gene, which has been reportedly associated with BPD. Methods We performed a case-control study to analyze the association between rs5177 single-nucleotide polymorphism in the LRP8 gene plus the single-nucleotide polymorphism rs11756438 in the CEP85L gene and schizophrenia in the Iranian population. The genotype for rs5177 was determined by ARMS PCR method, while for rs11756438 genotype, it was determined by PCR-RFLP method after which statistical analysis was performed for each polymorphism. In rs5177, the CC genotype was susceptible to the disease while G allele was associated with disease protection. Results and Conclusion In rs11756438, the AA genotype was associated with disease susceptibility, while allele A did not have a significant association with the disease.

MicroRNAs association with azoospermia, oligospermia, asthenozoospermia, and teratozoospermia: a systematic review.

Infertility is a major health problem across the world. One of the main reasons for male infertility are defects in sperm. Semen analysis is the most common test utilized to evaluate male fertility and since it suffers from multiple drawbacks, reproduction scientists have tried to find new molecular markers for detecting sperm defects. MicroRNAs (miRNAs) are small molecules in cells which take part in regulating gene expression. Various studies have confirmed miRNAs to have a role in defining multiple sperm characteristics, including sperm count, motility, and morphology. In this paper, we have systematically reviewed the role of miRNAs in infertile men with sperm defects including azoospermia, oligospermia, asthenozoospermia, and teratozoospermia. Also, we have assembled various bioinformatics tools to come up with a pipeline for predicting novel miRNAs which could possibly participate in sperm count, motility, and morphology. Also, related KEGG and GO terms for predicted miRNAs have been included in order to highlight their role in sperm function. Our study emphasizes the potential role of miRNAs in male infertility and provides a general overview for future studies aiming to find robust molecular markers for this condition.

A new report of autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) with a homozygous pattern from Iran.

Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) is an autosomal dominant autoinflammatory disease characterized by episodic skin, musculoskeletal, ophthalmic and gastrointestinal tract symptoms. Here we report an 11-year-old girl with a history of repeated episodes of fever, myalgia, arthralgia, abdominal pain, and urticarial rash in the trunk and limbs. Chest and pelvic X-Ray, sacroiliac joints MRI, brain MRI and abdominal CT scan were normal. Anti-nuclear antibody, Rheumatoid factor, cryoglobulin, ANCA/PR3, p-ANCA/MPO, anti-smooth muscle antibody and anti-mitochondrial antibody were negative. Serology for cytomegalovirus, Epstein-Barr, hepatitis B, hepatitis C, and HIV viruses was negative. Serum immunoglobulins were in the normal range. Genetic analysis for familial Mediterranean fever syndrome was negative. Whole exome sequencing was carried out to identify the genetic cause of our patient. We identified a homozygous missense variant (c.579C > G, p. His193Gln) in exon 7 of the PLCG2 gene. Bioinformatic analysis and clinical symptoms suggests this variant to be pathogenic in the homozygous state for APLAID and thus probably acting in an autosomal recessive manner. Our bioinformatic analysis also showed this novel mutation to have detrimental effects on the 3D structure of the PLCG2 protein, which is well conserved among many other similar species.

Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy.

Background X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families. Methods Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species. Results One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.

Features, genetics and their correlation in Jalili syndrome: a systematic review.

Jalili syndrome is a rare genetic disorder first identified by Jalili in Gaza. Amelogenesis imperfecta and cone-rode dystrophy are simultaneously seen in Jalili syndrome patients as the main and primary manifestations. Molecular analysis has revealed that the CNNM4 gene is responsible for this rare syndrome. Jalili syndrome has been observed in many countries around the world, especially in the Middle East and North Africa. In the current scoping systematic review we searched electronic databases to find studies related to Jalili syndrome. In this review we summarise the reported clinical symptoms, CNNM4 gene and protein structure, CNNM4 mutations, attempts to reach a genotype-phenotype correlation, the functional role of CNNM4 mutations, and epidemiological aspects of Jalili syndrome. In addition, we have analysed the reported mutations in mutation effect prediction databases in order to gain a better understanding of the mutation's outcomes.

RIT2: responsible and susceptible gene for neurological and psychiatric disorders.

RIT2 gene was recently introduced as a susceptibility gene in neurological disorders, a group of major problems in human society affecting millions of people worldwide. Several variants, including single nucleotide polymorphisms and CNVs, have been identified and studied in different populations. In this review, we have summarized the studies relevant to the RIT2 gene and its related disorders, including Parkinson's disease, schizophrenia, and autism. The protein product of RIT2 is a member of the Ras superfamily that plays important roles in many vital cellular functions, such as differentiation and survival. We have also investigated the protein network of the RIT2 protein and the diseases related to members of this network so as to obtain some clues for future studies by identifying the molecular pathophysiology of neurological disorders and revealing new possible disorders related to RIT2.