Abstract
Objectives and study: ATP8B1 deficiency is an autosomal recessive liver disease caused by
mutations in the ATP8B1 gene. Clinical symptoms range from intermittent (benign recurrent
intrahepatic cholestasis; BRIC) to progressive intrahepatic cholestasis (progressive familial
intrahepatic cholestasis; PFIC). Current therapeutic options for the more severe phenotype (PFIC) are
insufficient. For this group of patients, the development of targeted compounds for mutation-specific
therapy might be a promising new strategy. ATP8B1 mutation p.I661T, the most frequent mutation in
European patients, results in protein misfolding and impaired targeting to the plasma membrane.
Similarly, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene,
associated with cystic fibrosis, impair protein folding and trafficking. The aim of this study was to
investigate whether compounds that rescue CFTR F508del trafficking are also capable of improving
p.I661T-ATP8B1 plasma membrane expression.
Methods: Effect of CFTR corrector compounds on plasma membrane expression of p.I661T- ATP8B1
was evaluated by cell surface biotinylation and immunofluorescence.
Results: The clinically-approved compounds, 4-phenylbutyric acid (4-PBA), suberoylanilide
hydroxamic acid (SAHA) and N-butyldeoxynojirimycin (NB-DNJ) improved p.I661T-ATP8B1 plasma
membrane targeting. The pre-clinical CFTR correctors C4, C5, C13 and C17 also significantly
increased plasma membrane expression of p.I661T-ATP8B1. SAHA and compound C17 upregulated
ATP8B1 transcription. p.I661T-ATP8B1 was partly targeted to the canalicular membrane in polarized
cells, which became more evident upon treatment with SAHA and/or C4. Combination therapy of
SAHA and compound C4 resulted in an additional improvement of ATP8B1 cell surface abundance.
Conclusion: This study shows that several compounds, previously identified as CFTR correctors,
improve expression of p.I661T-ATP8B1 at the plasma membrane in vitro. Hence, these compounds
may be suitable to be part of a future therapy for ATP8B1 deficiency as well as other genetic disorders
associated with protein misfolding.
mutations in the ATP8B1 gene. Clinical symptoms range from intermittent (benign recurrent
intrahepatic cholestasis; BRIC) to progressive intrahepatic cholestasis (progressive familial
intrahepatic cholestasis; PFIC). Current therapeutic options for the more severe phenotype (PFIC) are
insufficient. For this group of patients, the development of targeted compounds for mutation-specific
therapy might be a promising new strategy. ATP8B1 mutation p.I661T, the most frequent mutation in
European patients, results in protein misfolding and impaired targeting to the plasma membrane.
Similarly, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene,
associated with cystic fibrosis, impair protein folding and trafficking. The aim of this study was to
investigate whether compounds that rescue CFTR F508del trafficking are also capable of improving
p.I661T-ATP8B1 plasma membrane expression.
Methods: Effect of CFTR corrector compounds on plasma membrane expression of p.I661T- ATP8B1
was evaluated by cell surface biotinylation and immunofluorescence.
Results: The clinically-approved compounds, 4-phenylbutyric acid (4-PBA), suberoylanilide
hydroxamic acid (SAHA) and N-butyldeoxynojirimycin (NB-DNJ) improved p.I661T-ATP8B1 plasma
membrane targeting. The pre-clinical CFTR correctors C4, C5, C13 and C17 also significantly
increased plasma membrane expression of p.I661T-ATP8B1. SAHA and compound C17 upregulated
ATP8B1 transcription. p.I661T-ATP8B1 was partly targeted to the canalicular membrane in polarized
cells, which became more evident upon treatment with SAHA and/or C4. Combination therapy of
SAHA and compound C4 resulted in an additional improvement of ATP8B1 cell surface abundance.
Conclusion: This study shows that several compounds, previously identified as CFTR correctors,
improve expression of p.I661T-ATP8B1 at the plasma membrane in vitro. Hence, these compounds
may be suitable to be part of a future therapy for ATP8B1 deficiency as well as other genetic disorders
associated with protein misfolding.
| Original language | English |
|---|---|
| Pages | 502 |
| Number of pages | 1 |
| Publication status | Published - 27 May 2016 |
| Event | 49th Annual ESPGHAN Meeting - Megaron International Conference Center, Athens, Greece Duration: 25 May 2016 → 28 May 2016 http://www.espghan.org/meetings-and-events/annual-meetings/previous-meetings/ |
Conference
| Conference | 49th Annual ESPGHAN Meeting |
|---|---|
| Country/Territory | Greece |
| City | Athens |
| Period | 25/05/16 → 28/05/16 |
| Internet address |