Autosomal Recessive Renal Tubular Dysgenesis Caused by a Founder Mutation of Angiotensinogen

Abstract

Introduction: 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.Methods: 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.Results: 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 deletionþ9bp 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. Conclusion: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.

Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios

“…In addition, the c.857-619_1269 + 243delinsTTGCCTTGC mutation identified in the AGT gene was previously reported in seven Taiwanese families (Ma et al, 2019;Min-Hua et al, 2020). This suggests that this allele may be the result of a founder effect.…”

“…The c.856 + 1G > T variant is not observed at a significant frequency in large population cohorts ( Genomes Project Consortium, Auton et al, 2015 ; Lek et al, 2016 ). In addition, the c.857-619_1269 + 243delinsTTGCCTTGC mutation identified in the AGT gene was previously reported in seven Taiwanese families ( Ma et al, 2019 ; Min-Hua et al, 2020 ). This suggests that this allele may be the result of a founder effect.…”

Effect of Hydrocortisone on Angiotensinogen (AGT) Mutation–Causing Autosomal Recessive Renal Tubular Dysgenesis

“…Seven different mutations including 5 missense, 1 nonsense, and 1 large deletion mutations on AGT were identified. All of the mutants were located in the serpine domain [ 1 , 8 , 14 , 21 ]. Of note, the serpine domain is critical for the AGT cleavage by renin [ 18 , 22 , 23 ].…”

“…This mutation led to the exclusion of exon 3 and 4, and generated the truncated AGT (1–292 amino acids). A potentially candidate binding motif (LQDLL) of nuclear receptor was excluded by this mutation ( Figure 1 ) [ 14 ].…”

“…Recently, we have reported six patients with ARRTD caused by AGT (angiotensinogen) mutation from six unrelated families [ 14 ]. This homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT resulted in the skipping of exons and the generation of truncated protein (1–292 amino acids) as well as diminished serum AGT, Ang I, and Ang II.…”