These studies quantitatively show that the autosomal-dominant gene mutations responsible for UMOD-associated kidney disease cause a profound reduction of THP excretion.
Mutations in nephrin (NPHS1), podocin (NPHS2), laminin β2 (LAMB2), and α-actinin-4 (ACTN4) have been shown to induce ER stress in HEK293 cells and podocytes in hereditary nephrotic syndromes; various founder mutations in collagen IV α chains (COL4A) have been demonstrated to activate podocyte ER stress in collagen IV nephropathies; and mutations in uromodulin (UMOD) have been reported to trigger tubular ER stress in autosomal dominant tubulointerstitial kidney disease.
Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance.
In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.
Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease.
These studies quantitatively show that the autosomal-dominant gene mutations responsible for UMOD-associated kidney disease cause a profound reduction of THP excretion.
In addition, approximately two-thirds of the known mutations lead to a cysteine amino acid change in uromodulin, and all such variants have been shown to cause UMOD-associated kidney disease.
These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes.
A total of 646 individuals, 208 with T2DM without evidence of kidney disease (DM), 221 with DN and 217 healthy controls (HC) were genotyped for UMOD variant rs4293393T>C by restriction fragment length polymorphism.
Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease.
No single nucleotide polymorphisms in the ACE2 or AGTR1 genes were significantly associated with nephropathy when analysed either by genotype or allele frequencies.
In order to replicate these findings we performed PCR-based genotyping for the A1166-->C DNA polymorphism and the CA repeat at the 3' end of the angiotensin II (type 1) receptor gene employing validated groups of type 1 diabetic patients with (cases, n = 95) and without (controls, n = 97) nephropathy.
The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM.
Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59-0.94).
Renin-angiotensin-aldosterone system inhibitors (RAASIs), including angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases.
The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001).
Altogether, these data suggest that this homozygous TTC21Bp.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.