Project description:Denys-Drash syndrom is a rare disease. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of kidney tissue cells in an infant with Denys-Drash syndrom.
Project description:COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved renal function in vivo. These results partly clarified the pathogenesis of renal injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
Project description:Alport syndrome is a glomerular disease. To understand the disease progression of alport syndrome and potential therapeutical effects of hEV derived from AFSCs, we performed spatial transcriptomics to profile the heterogeniety of cell populations in kidneys of mouse of AS through disease progression and hEV treated AS mice as well. Our analysis sheds light on key functional parts of the kidney responsible in disease progression as well as potential targets of hEV therapy.
Project description:Human velocardiofacial syndrom/DiGeorg (VCFS/DGS) syndrom is a complex developmental disease with various expression of a large number of phenotypes. Craniofacial, cardiac, behavioural and endocrinological phenotypes are cardinal symptoms liked to the 22Q11.2 deletion occuring in 1/4.000 births. Several genes located within the 1.5 to 3 Mb deletion resemble a number of phenotypes demonstrated in mouse models for these genes including the endothelin receptor A (Ednra) gene. This is the first report on gene dosage effects observed in a dominant mouse model carrying an EdnraY129F point-mutation. EdnraY129F/+ mice are viable despite a strong cardiac phenotype alike to Fallot's tetralogy concomitant with cardiofacial, otolaryngeal phenotypes and deafness.
Project description:Human velocardiofacial syndrom/DiGeorg (VCFS/DGS) syndrom is a complex developmental disease with various expression of a large number of phenotypes. Craniofacial, cardiac, behavioural and endocrinological phenotypes are cardinal symptoms liked to the 22Q11.2 deletion occuring in 1/4.000 births. Several genes located within the 1.5 to 3 Mb deletion resemble a number of phenotypes demonstrated in mouse models for these genes including the endothelin receptor A (Ednra) gene. This is the first report on gene dosage effects observed in a dominant mouse model carrying an EdnraY129F point-mutation. EdnraY129F/+ mice are viable despite a strong cardiac phenotype alike to Fallot's tetralogy concomitant with cardiofacial, otolaryngeal phenotypes and deafness. Total RNA obtained from 4 male heterzygote and 4 male wildtype mice
Project description:Alport mouse model (Col4a5) have been submitted for proteomic analysis. Glomeruli have been isolated from mouse kidneys, extracellular matrix has been enriched and analysed by mass spectrometry.
Project description:Large Xq22.3 deletion in Czech family inherited from unaffaceted mother leading to manifestation of X-linked contiguous gene deletion syndrome known as Alport syndrome with intellectual disability (ATS-ID) or AMME complex (OMIM #300194)