Absence of cell surface expression of human ACE leads to perinatal death.

Annie Michaud,Pierre Corvol,Nicole Quenech'Du,Marie-Claire Gubler,Vincent Morinière,Geoffrey Masuyer,Olivier Gribouval,K Ravi Acharya

doi:10.1093/hmg/ddt535

Abstract

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 and R828H) and two truncated mutants (Q1136X and 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 modelling, which suggested some important structural alterations such as disruption of intra-molecular non-covalent interactions (e.g. salt bridges).

Highlights

Angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A) is a metallopeptidase which belongs to the gluzincin family of metalloproteases
There was a massive increase in the patient plasma renin activity (PRA) and a marked decrease in his angiotensinogen concentration, which was 10– 20 times lower than that of his parents and controls, respectively
Congenital malformations have been reported in infants with fetal exposure during the first trimester alone [29] but the fetal effects of angiotensin I-converting enzyme (ACE) inhibitors appear to be more marked during late pregnancy and are attributed to severe hypotension and renal hypoperfusion [30,31]

Summary

Introduction

Angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A) is a metallopeptidase which belongs to the gluzincin family of metalloproteases. ACE cleaves the C-terminal His-Leu dipeptide from angiotensin I (Ang I) to produce the potent vasopressor octapeptide, Ang II. It inactivates bradykinin (BK) by the sequential removal of two C-terminal dipeptides. ACE is implicated in blood pressure regulation, water and salt metabolism, cardiac and renal function and in other non-traditional biological functions, as reviewed recently in depth by Bernstein et al [1]. ACE is a target for inhibiting the renin-angiotensin system (RAS). ACE inhibitors have shown their efficacy in the treatment of hypertension, congestive heart failure and diabetic nephropathy and are able to prevent cardiovascular events in patients at risk

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