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 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.
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.