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Kidney Week

Abstract: PO1611

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

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Tseng, Min-hua, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • Lin, Shih-Hua P., Tri-Service General Hospital, Taipei, Taiwan
Background

Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in AGT, REN, ACE, and AGTR is a very rare but fatal disorder with incomplete knowledge about pathogenesis and a lack of therapeutic options.

Methods

We report six Taiwanese with ARRTD from six unrelated families diagnosed by renal histology. Clinical features, prevalence of carrier heterozygosity, pathogenesis, and potential rescue therapy were examined.

Results

All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. AGT (Angiotensinogen) protein levels were diminished in the liver along with reduced serum AGT, angiotensin I (Ang I) and II (Ang II) levels. Neonatal demise occurred in all but one. All carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT. 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 (1-295 amino acids). In silico modeling revealed a diminished interaction between mutant AGT and renin, and proximity ligation assay demonstrated a significant decrease in the amount of this truncated protein.

Conclusion

This AGT mutation leads to the diminished interaction with renin and decreased Ang I and II generation. Hydrocortisone may potentially rescue the cases of ARRTD caused by this truncated AGT.