Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized most often by perinatal death. It is due to the inactivation of any of the major genes of the renin-angiotensin system (RAS), one of which is the angiotensin I-converting enzyme (ACE). ACE is present as a tissue-bound enzyme and circulates in plasma after its solubilization. In this report, we present the effect of different ACE mutations associated with RTD on ACE intracellular trafficking, secretion and enzymatic activity. One truncated mutant, R762X, responsible for neonatal death, was found to be an enzymatically active, secreted form, not inserted in the plasma membrane. In contrast, another mutant, R1180P, was compatible with life after transient neonatal renal insufficiency. This mutant was located at the plasma membrane and rapidly secreted. These results highlight the importance of tissue-bound ACE versus circulating ACE and show that the total absence of cell surface expression of ACE is incompatible with life. In addition two missense mutants (W594R, R828H) and two truncated mutants (Q1136X, G1145AX) were also studied. These mutants were neither inserted in the plasma membrane nor secreted. Finally, the structural implications of these ACE mutations were examined by molecular modeling, which suggested some important structural alterations such as disruption of intra-molecular non-covalent interactions (eg. salt bridges).
Michaud, A., Acharya, K. R., Masuyer, G., Quenech'du, N., Gribouval, O., Morinière, V., ... Corvol, P. (2014). Absence of cell surface expression of human ACE leads to perinatal death. Human Molecular Genetics, 23(6), 1479-1491. https://doi.org/10.1093/hmg/ddt535