Abstract：
UNASSIGNED: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms.
UNASSIGNED: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project.
UNASSIGNED: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated.
UNASSIGNED: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
UNASSIGNED: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project.
UNASSIGNED: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated.
UNASSIGNED: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
摘要：
■常染色体隐性遗传肾小管发育不全是一种罕见的，通常致命的REN（肾素）-血管紧张素系统遗传性疾病。在这里，我们报告了一名青少年个体经历了一种未知的慢性肾脏疾病,旨在提供对疾病机制的新见解.
■对与肾脏疾病相关的基因组进行外显子组测序。通过血液中的综合生化分析评估REN-血管紧张素系统。通过定量聚合酶链反应和肾活检样品的原位杂交确定原代肾小管细胞中的REN表达。杂合和双等位基因有害变体的等位基因频率通过基因组英格兰100,000基因组项目的分析来确定。
■患者在妊娠期间检测到羊水过少后过早分娩。出生后,患者已从三级急性肾损伤中恢复,但随着时间的推移发展为慢性肾脏病G3b期.外显子组测序揭示了以前报道的致病性纯合错义变异，p.(Arg375Gln)，在AGT（血管紧张素原）基因中。血液AGT浓度很低,但血浆REN浓度和肾活检基因表达，血管,肾小管细胞显示REN强烈上调。血液中的血管紧张素II和醛固酮没有异常升高。
■肾小管发育不全可能表现为具有可变表型的慢性肾脏疾病，需要广泛的遗传分析进行诊断。对AGT突变患者的肾素-血管紧张素系统的功能分析揭示了有关肾脏血管和肾小管细胞以及血浆中REN代偿性上调的新见解，以响应作为AngII来源的AGT底物的消耗（与肝AGT沉默治疗高血压类似）。
■对与肾脏疾病相关的基因组进行外显子组测序。通过血液中的综合生化分析评估REN-血管紧张素系统。通过定量聚合酶链反应和肾活检样品的原位杂交确定原代肾小管细胞中的REN表达。杂合和双等位基因有害变体的等位基因频率通过基因组英格兰100,000基因组项目的分析来确定。
■患者在妊娠期间检测到羊水过少后过早分娩。出生后,患者已从三级急性肾损伤中恢复,但随着时间的推移发展为慢性肾脏病G3b期.外显子组测序揭示了以前报道的致病性纯合错义变异，p.(Arg375Gln)，在AGT（血管紧张素原）基因中。血液AGT浓度很低,但血浆REN浓度和肾活检基因表达，血管,肾小管细胞显示REN强烈上调。血液中的血管紧张素II和醛固酮没有异常升高。
■肾小管发育不全可能表现为具有可变表型的慢性肾脏疾病，需要广泛的遗传分析进行诊断。对AGT突变患者的肾素-血管紧张素系统的功能分析揭示了有关肾脏血管和肾小管细胞以及血浆中REN代偿性上调的新见解，以响应作为AngII来源的AGT底物的消耗（与肝AGT沉默治疗高血压类似）。
