The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
Context Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome). Case description This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G>A p.Arg246Gln, c.3982G>C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2–/– mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland. Conclusion We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.
Breast cancer (Bc) is the most commonly diagnosed cancer worldwide and a major health concern in egypt. There is a known association between pathogenic variants identified in breast cancer susceptibility gene (BRCA)1 and 2 and the risk of developing Bc. However, the number of studies investigating mutations in BRCA1 and BRCA2 in egypt remains limited. Thus, the aim of the present study was to investigate the frequency of BRCA1 and BRCA2 variants in patients with Bc and their relatives. For this purpose, 11 families (11 patients and 16 relatives) were included in the present study. BRCA1 and BRCA2 variants were investigated using the ion S5 next-generation sequencer. it was found that pathogenic variants were more frequent in patients with familial Bc (FBc) than in those with sporadic Bc, with 71% of variants in BRCA2, including the first reported identification of c.9089del, c.5583_5584dup, c.8243G>A and c.7976G>A pathogenic variants in Egyptian patients with BC. Pathogenic variants in relatives were confined to FBC c.1278delA, c.1960_1961del, and c.1224delT, with a higher incidence of variants of uncertain significance (VUS), such as BRCA2 intron 2 c.68-16delT. of note, two cold spot benign variants, c.3113A>G and c.4837A>G, were repeatedly found (67%) in patients and relatives. in conclusion, to the best of our knowledge, novel pathogenic variants and VUS in Egyptian patients with BC and their high-risk relatives were identified for the first time in the present study. These findings should be integrated with other genomic data concerning egyptian families and carefully interpreted during genetic counseling.
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