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Abstract：
UNASSIGNED: Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in AGT, REN, ACE, and AGTR is a very rare but fatal disorder with an unknown prevalence.
UNASSIGNED: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined.
UNASSIGNED: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT, which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous AGT mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. In silico modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels.
UNASSIGNED: This AGT mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.
UNASSIGNED: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined.
UNASSIGNED: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT, which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous AGT mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. In silico modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels.
UNASSIGNED: This AGT mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.
摘要：
■由AGT失活突变引起的常染色体隐性遗传肾小管发育不全（ARRTD），REN,ACE,AGTR是一种非常罕见但致命的疾病，患病率未知。
■我们报告了6个台湾患者ARRTD患者，来自6个无关的家族，通过肾组织学诊断。临床特征,结果,并检查了携带者杂合性的患病率。
■所有患者均表现出产前羊水过少，产后无尿,肺发育不全,和干预难以治疗的深度低血压。血管紧张素原（AGT）蛋白水平在肝脏减少，随着血清AGT的减少，血管紧张素I（AngI）和血管紧张素II（AngII）水平。除1例以外，所有病例均发生新生儿死亡。所有个体在AGT中携带相同的纯合E3_E4del：2870bp缺失+9bp插入，导致截短的蛋白质（1-292个氨基酸）。该杂合AGT突变的等位基因频率约为1.2％（6/500），这表明ARRTD在台湾可能并不罕见。这种突变导致编码AGTserpin结构域的外显子的跳跃，这对于肾素相互作用和截短蛋白的产生很重要。计算机模拟显示，突变AGT和肾素之间的相互作用减弱。一名患者在接受大剂量氢化可的松治疗后存活，随着深度低血压的解决，伴随着血清AGT的增加，AngI,和AngII水平。
■这种AGT突变可能导致与肾素的相互作用减少，AngI和AngII的产生减少。氢化可的松可能会挽救由这种截短的AGT引起的ARRTD病例。
■我们报告了6个台湾患者ARRTD患者，来自6个无关的家族，通过肾组织学诊断。临床特征,结果,并检查了携带者杂合性的患病率。
■所有患者均表现出产前羊水过少，产后无尿,肺发育不全,和干预难以治疗的深度低血压。血管紧张素原（AGT）蛋白水平在肝脏减少，随着血清AGT的减少，血管紧张素I（AngI）和血管紧张素II（AngII）水平。除1例以外，所有病例均发生新生儿死亡。所有个体在AGT中携带相同的纯合E3_E4del：2870bp缺失+9bp插入，导致截短的蛋白质（1-292个氨基酸）。该杂合AGT突变的等位基因频率约为1.2％（6/500），这表明ARRTD在台湾可能并不罕见。这种突变导致编码AGTserpin结构域的外显子的跳跃，这对于肾素相互作用和截短蛋白的产生很重要。计算机模拟显示，突变AGT和肾素之间的相互作用减弱。一名患者在接受大剂量氢化可的松治疗后存活，随着深度低血压的解决，伴随着血清AGT的增加，AngI,和AngII水平。
■这种AGT突变可能导致与肾素的相互作用减少，AngI和AngII的产生减少。氢化可的松可能会挽救由这种截短的AGT引起的ARRTD病例。
