The novel ACE Q1069R mutation causes renal tubular dysgenesis via impaired proteostasis and ER retention, which can be partially rescued in vitro by lowering temperature, demonstrating that the enzyme's catalytic activity remains intact.
ACE Q1069R may underlie renal tubular dysgenesis via ER retention; hypothesis-generating for proteostasis rescue but should not change practice.
Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.
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Oliveira et al. (2011) studied this question.
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