الفهرس 
GENETICS OF NEPHROTIC SYNDROMEOnly 14 pages are availabe for public view
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Abstract
G
enetically determined abnormalities in the structure of 2 membrane components – collagen type IV and _2-laminin – result in glomerular damage. Mutation of the genes coding for collagen type IV lead to the thin-basement membrane nephropathy (TBMN) and Alport syndromes. In the latter disease, a mutation in one of 4 genes coding for collagen chains is tightly linked to the symptoms of progressive nephropathy with severe hematuria and proteinuria, leading to the terminal stage of chronic kidney disease.
Loss-of-function mutations in the LMX1B gene, encoding for the transcription factor regulating the expression of COL4A3 (type IV collagen 3 chain), COL4A4 (type IV collagen 4 chain), NPHS1 (nephrin), NPHS2 (podocin), and CD2AP, are related to the symptoms of nail-patella syndrome (NPS).
Current data suggest that the pathogenesis of NPS is related to abnormalities in the structure and filtration function of the slit diaphragm. This is inferred from the fact that LMX1B codes for the transcription factor regulating the expression of the genes encoding the key slit diaphragm proteins: nephrin, podocin and CD2AP.
Mutations of the LAMB2 gene for 2 laminin chain are the cause of Pierson syndrome, inherited in the autosomal recessive pattern. The 2 chain of this protein is present in the GBM as a component of the laminin-11 isoform (5:2:1), vital for anchoring and differentiation of podocytes. A lack of the functional _2 chain results in a disturbance of 11-laminin function, leading to the nephrotic syndrome resistant to treatment.
Podocytes with their filtration slit diaphragm are a key element of the glomerular filtration barrier. Microtubules and intermediate filaments are some of the characteristic features of its cytoarchitecture, with actin cytoskeleton within foot processes. A number of proteins attached to actin filaments (such as talin, paxillin and vinculin) mediate the link between cytoskeleton and GBM integrins. The actin cytoskeleton is additionally linked to the filtration slit diaphragm by catenins, CD2AP and ZO-1 protein.
Mutations of the ACTN4 gene, coding for -actinin-4, are related to the autosomal dominant focal segmental glomerulosclerosis (FSGS) type 1. Onset of the disease is typically recorded in adolescence or early childhood, and results in the treatment-resistant non-nephrotic proteinuria, and slow progression to chronic kidney disease.
Among various causes of monogenic glomerulonephropathies, mutations of the mitochondrial genome are also to be considered. A typical example of mitochondrial cytopathy is the one caused by the A3243G transition of the MTTL1 gene for leucine tRNA. This transition results in a respiratory chain defect with podocyte malfunction, leading to FSGS.
It is worthy of note that a glomerular disease may be caused not only by mitochondrial mutations, but also by lesions of another organelle, i.e. the lysosome, with Fabry disease being a model example. The Fabry disease, an inborn error of glycosphingolipid catabolism, is caused by loss of function” mutations of the GALA gene encoding -galactosidase A.
The Wilms’ tumor gene (WT1) is located on chromosome 11p13. WT1 is composed of 10 exons and encodes a protein with 4 zinc fingers. Regulated expression of WT1 is one of the major requirements for normal renal and genital development but mechanisms that regulate WT1 expression are still unclear.
WT1 is expressed in podocytes, from the capillary loop stage of development onwards, and WT1 is required for podocyte function. WT1 mutations are typically seen in sporadic Wilms’ tumors and occur frequently in association with Frasier and Denys-Drash syndromes.
Nephrin is encoded by the NPHS1 gene located on chromosome 1q13.1. NPHS1 mutations result in the congenital nephrotic syndrome of the Finnish type (CNF), which remains a rare autosomal recessive disease, occurring predominantly in Finland.
Mutations in the NPHS2 gene encoding podocin have been identified as a cause of autosomal recessive steroid- resistant nephrotic syndrome.
NPHS2 mutations result in a dysfunction of the glomerular filtration barrier. Podocin represents an essential component of the slit diaphragm and a close interactor of nephrin.
Their results clearly demonstrated that 2/3 of cases of such a nephrotic syndrome can be explained by mutations in the 4 genes only, and NPHS2 mutations identified in 37.5% of all of the families are the most common cause of nephritic syndrome manifesting in the first year of life, accounting for more than half of all causative mutations.