Kidd Kendrah, Vylet'al Petr, Schaeffer Céline, Olinger Eric, Živná Martina, Hodaňová Kateřina, Robins Victoria, Johnson Emily, Taylor Abbigail, Martin Lauren, Izzi Claudia, Jorge Sofia C, Calado Joaquim, Torres Rosa J, Lhotta Karl, Steubl Dominik, Gale Daniel P, Gast Christine, Gombos Eva, Ainsworth Hannah C, Chen Ying Maggie, Almeida Jorge Reis, de Souza Cintia Fernandes, Silveira Catarina, Raposeiro Rita, Weller Nelson, Conlon Peter J, Murray Susan L, Benson Katherine A, Cavalleri Gianpiero L, Votruba Miroslav, Vrbacká Alena, Amoroso Antonio, Gianchino Daniela, Caridi Gianluca, Ghiggeri Gian Marco, Divers Jasmin, Scolari Francesco, Devuyst Olivier, Rampoldi Luca, Kmoch Stanislav, Bleyer Anthony J
Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Research Unit of Rare Diseases, Department of Pediatric and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Kidney Int Rep. 2020 Jul 3;5(9):1472-1485. doi: 10.1016/j.ekir.2020.06.029. eCollection 2020 Sep.
Autosomal dominant tubulo-interstitial kidney disease due to mutations (ADTKD-) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival.
An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, < 0.001).
The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD.
We report the clinical characteristics associated with 125 mutations. Male gender and a new score predict age of ESKD.
由突变引起的常染色体显性遗传性肾小管间质性肾病（ADTKD-）是一种罕见疾病，与终末期肾病（ESKD）的发病年龄高度可变有关。位于该基因启动子区的rs4293393次要等位基因在19%的人群中存在，可使尿调节蛋白的产生下调约50%，并可能影响ESKD的发病年龄。本研究的目的是更好地了解ADTKD-的遗传和临床特征，并进行孟德尔随机化研究，以确定rs4293393次要等位基因是否与更好的肾脏存活率相关。
一个国际合作团队收集了来自249个家庭的722名患病个体的临床和遗传数据，这些家庭中有125个突变，包括28个新突变。ESKD的中位年龄为47岁。男性进展为ESKD的风险要高得多（风险比1.78，<0.001）。
rs4293393次要等位基因的等位基因频率仅为11.6%，而预期为19%（<0.01），导致哈迪-温伯格不平衡，无法进行孟德尔随机化实验。发现一个反映尿调节蛋白突变体转运缺陷严重程度的评分是ESKD发病年龄的一个有前景的预测指标。
我们报告了与125个突变相关的临床特征。男性性别和一个新的评分可预测ESKD的发病年龄。
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