Identification of a Novel Deletion Variant (c.2999_3005delTGTGTGT/p.Asn1000SerfsTer4) in NPHP4 Associated With Nephronophthisis-4.

BACKGROUND: Nephronophthisis-4 (NPHP4) is an inherited renal ciliopathy described by renal fibrosis and progressive impairment of kidney function. This study aimed to investigate the genetic basis and clinical manifestations of NPHP4 in two Iranian siblings. METHODS: The proband was a 27-year-old male with features of end-stage renal disease, including anemia, uremia, polyuria, and polydipsia. It is worth mentioning that he has a 22-year-old sister with a similar presentation. Clinical diagnosis procedures, such as renal biopsy, brain imaging, blood and urine tests, cardiac evaluation, ophthalmic inspection, and auditory function assessment, were carried out to evaluate organ involvement and potential comorbidities. Whole-exome sequencing (WES) and segregation analysis were performed to identify and confirm genetic variants associated with the condition. Computational variant analysis was conducted to evaluate the pathogenicity of the candidate variant. Furthermore, the SWISS-MODEL server was utilized for protein modeling. RESULTS: The brain, cardiac, ocular, and auditory functions were normal. Renal biopsy of the proband showed chronic interstitial inflammation and fibrosis. We found a novel homozygous 7-base pair deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4 by WES. Segregation analysis confirmed homozygosity for the NPHP4 variant in affected individuals and heterozygous carrier status in parents, supporting autosomal recessive inheritance. 3D protein modeling indicated significant structural changes due to the variant. CONCLUSION: This study expands the genetic causes and phenotypic spectrum of nephronophthisis-4 and reveals the importance of genetic analysis in diagnosing and managing rare inherited kidney disorders, particularly those involving consanguinity.

Circular RNAs: Epigenetic regulators of PTEN expression and function in cancer.

Epigenetic regulation of gene expression, without altering the DNA sequence, is involved in many normal cellular growth and division events, as well as diseases such as cancer. Epigenetics is no longer limited to DNA methylation, and histone modification, but regulatory non-coding RNAs (ncRNAs) also play an important role in epigenetics. Circular RNAs (circRNAs), single-stranded RNAs without 3' and 5' ends, have recently emerged as a class of ncRNAs that regulate gene expression. CircRNAs regulate phosphatase and tensin homolog (PTEN) expression at various levels of transcription, post-transcription, translation, and post-translation under their own regulation. Given the importance of PTEN as a tumor suppressor in cancer that inhibits one of the most important cancer pathways PI3K/AKT involved in tumor cell proliferation and survival, significant studies have been conducted on the regulatory role of circRNAs in relation to PTEN. These studies will be reviewed in this paper to better understand the function of this protein in cancer and explore new therapeutic approaches.

Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study.

Background and Aims: Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by pathogenic variants of the fibrillin-1-encoding FBN1 gene that commonly affects the cardiovascular, skeletal, and ocular systems. This study aimed to evaluate the clinical features and genetic causes of the MFS phenotype in a large Iranian family. Methods: Seventeen affected family members were examined clinically by cardiologists and ophthalmologists. The proband, a 48-year-old woman with obvious signs of MFS, her DNA sample subjected to whole-exome sequencing (WES). The candidate variant was validated by bidirectional sequencing of proband and other available family members. In silico analysis and molecular modeling were conducted to determine the pathogenic effects of the candidate variants. Results: The most frequent cardiac complications are mitral valve prolapse and regurgitation. Ophthalmic examination revealed iridodonesis and ectopic lentis. A heterozygous missense variant (c.2179T>C/p.C727R) in exon 19 of FBN1 gene was identified and found to cosegregate with affected family members. Its pathogenicity has been predicted using several in silico predictive algorithms. Molecular docking analysis indicated that the variant might affect the binding affinity between FBN1 and LTBP1 proteins by impairing disulfide bond formation. Conclusion: Our report expands the spectrum of the Marfan phenotype by providing details of its clinical manifestations and disease-associated molecular changes. It also highlights the value of WES in genetic diagnosis and contributes to genetic counseling in families with MFS.

Investigation of genes and pathways involved in breast cancer subtypes through gene expression meta-analysis.

BACKGROUND: Molecular-based studies have revealed heterogeneity in Breast cancer BC while also improving classification and treatment. However, efforts are underway to distinguish between distinct subtypes of breast cancer. In this study, the results of several microarray studies were combined to identify genes and pathways specific to each BC subtype. METHODS: Meta-analysis of multiple gene expression profile datasets was screened to find differentially expressed genes (DEGs) across subtypes of BC and normal breast tissue samples. Protein-protein interaction network and gene set enrichment analysis were used to identify critical genes and pathways associated with BC subtypes. The differentially expressed genes from meta-analysis was validated using an independent comprehensive breast cancer RNA-sequencing dataset obtained from the Cancer Genome Atlas (TCGA). RESULTS: We identified 110 DEGs (13 DEGs in all and 97 DEGs in each subtype) across subtypes of BC. All subtypes had a small set of shared DEGs enriched in the Chemokine receptor bind chemokine pathway. Luminal A specific were enriched in the translational elongation process in mitochondria, and the enhanced process in luminal B subtypes was interferon-alpha/beta signaling. Cell cycle and mitotic DEGs were enriched in the basal-like group. All subtype-specific DEG genes (100%) were successfully validated for Luminal A, Luminal B, ERBB2, and Normal-like. However, the validation percentage for Basal-like group was 77.8%. CONCLUSION: Integrating researches such as a meta-analysis of gene expression might be more effective in uncovering subtype-specific DEGs and pathways than a single-study analysis. It would be more beneficial to increase the number of studies that use matched BC subtypes along with GEO profiling approaches to reach a better result regarding DEGs and reduce probable biases. However, achieving 77.8% overlap in basal-specific genes and complete concordance in specific genes related to other subtypes can implicate the strength of our analysis for discovering the subtype-specific genes.