Nejvíce citovaný článek - PubMed ID 35947615
An intermediate-effect size variant in UMOD confers risk for chronic kidney disease
INTRODUCTION: Although 10% of adults with chronic kidney disease (CKD) have a monogenic cause, the characteristics of monogenic CKD in older adults (aged ≥ 60 years) are less characterized. We aimed to assess the clinical and genetic spectrum of older adults with CKD and the clinical utility of genetic findings. METHODS: The diagnostic yield of clinically validated disease-causing variants and their type ("typical" vs. "later-onset" phenotypes) were analyzed in older patients with suspected monogenic CKD who were referred to an Irish registry according to predetermined criteria. Independent genetic diagnosis and kidney survival time predictors were analyzed using marginal logistic and Cox regression analyses. RESULTS: Two hundred sixty-five adults (from 202 families) were aged ≥ 60 years at the time of genetic testing, of which 74.3% (197/265) progressed to kidney failure. Diagnostic variants were found in 60.4% (122/202) families, including 39% of noncystic kidney disease families. Variants causing "later-onset" phenotypes were more prevalent in patients with disease-onset ≥ 60 years (56% vs. 8.3%; P ≤ 0.001), which include genetic variants in: IFT140, ALG5, ALG9, DNAJB11, COL4A5 in females, monoallelic COL4A3, and the UMOD p.Thr62Pro variant, associated with delayed onset of kidney failure compared with "typical" variants (hazard ratio: 0.52; 95% confidence interval: 0.27-0.98; P = 0.043). A family history of CKD and a priori cystic kidney disease diagnosis independently predicted genetic diagnosis (P ≤ 0.05). In 24% of older adults with positive results, the treatment plan was modified. CONCLUSION: In older patients with CKD, genetic testing revealed enriched variants associated with less-penetrant phenotypes, often with a family history of CKD, which affects clinical management.
- Klíčová slova
- CKD, MPS, monogenic, older, polycystic kidney disease,
- Publikační typ
- časopisecké články MeSH
The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.
- Klíčová slova
- Genetic diseases, Nephrology, Protein misfolding, Protein traffic,
- MeSH
- lidé MeSH
- membránové glykoproteiny metabolismus genetika MeSH
- mutace MeSH
- myši MeSH
- transport proteinů * MeSH
- uromodulin * metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- membránové glykoproteiny MeSH
- UMOD protein, human MeSH Prohlížeč
- Umod protein, mouse MeSH Prohlížeč
- uromodulin * MeSH
The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.
- Klíčová slova
- Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1, REN, UMOD,
- MeSH
- chronická renální insuficience * MeSH
- dospělí MeSH
- genetické testování * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace MeSH
- senioři MeSH
- uromodulin genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- uromodulin MeSH