Denys-Drash syndrome (DDS), caused by mutations in the WT1 gene affecting the third or second zinc finger, is characterized by a triad of glomerulopathy progressing rapidly to end-stage renal disease, male hermaphroditism, and Wilms tumor.
The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases.
Several reports have shown a high prevalence of mutations (75%) in the inverted formin gene (INF2) in patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype.
No CLCN5 mutations were detected.TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002).
Mutations in FN are associated with glomerulopathy, but when we studied mutant proteins, the single-nucleotide mutations had only minor effects on conformation and matrix assembly.
These data, together with a recent report associating mutations in the FN gene to a form of glomerulopathy, clearly show that mutations in constitutive exons or misregulation of alternatively spliced domains of the FN gene may have nonlethal pathological consequences.
For example, risk alleles in the gene encoding apolipoprotein L1 (APOL1) have been established as the most important factor in the high incidence of chronic glomerular diseases in African Americans.
Apolipoprotein L1 (APOL1) genetic variants are potent risk factors for glomerular disease, but one or more additional factors are required for expression of glomerular disease.
In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly.
Sequence changes (termed G1 and G2) in the APOL1 gene that restored its ability to kill T b rhodesiense also increase the risk of developing glomerular diseases and accelerate progression to end-stage kidney disease.
The definition of APOL1 nephropathy also confirms the long-held assumption by many clinicians that kidney disease attributed to hypertension in African populations represents an underlying glomerulopathy.