# Altered biosynthesis and function of ABCC6 in systemic mineralization disorders

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $310,288

## Abstract

Abstract
 The human ABCC6 ATP-Binding Cassette (ABC-) transporter has been implicated to play a role in
multiple human connective tissue diseases, including pseudoxanthoma elasticum (PXE). The loss of ABCC6
function putatively results in the loss of one or more circulatory factors that regulate the mineralization of elastic
tissues systemically. Multiple disease-causing mutations in ABCC6 have been identified in PXE patients, yet
their molecular impacts on ABCC6 structure and function are unknown. The work presented in this proposal is
directed at addressing several key questions that are fundamental to our understanding of the molecular
pathologies in ABCC6 and identifying mechanisms for targeted therapeutic development to correct these
defects, specifically: (1) How do mutations alter the biosynthesis and function of ABCC6? (2) Are there
mechanisms that can be used to correct these defects to restore protein function?
 Our preliminary data, systematically evaluating a large library of ABCC6 mutations, demonstrates that
mutations can be broadly grouped into multiple structural and mechanistic classes. Two categories result in
altered protein folding and are differentially distinguished by their effects on local and global protein structures.
The third category of mutation is putatively associated with altered protein function. These studies provide a
fundamental understanding of ABCC6 structure and function and novel insight into the molecular defects
associated with specific disease-causing mutations. Our preliminary data further suggest a mechanism(s) that
restores mutant ABCC6 biosynthesis and function. This mechanism of stabilization rescues multiple severe,
disease-causing mutants within ABCC6. Characterization of this rescue provides additional insight into the
biosynthesis of wildtype ABCC6 and the defects associated with mutant ABCC6. In addition, these studies lay
the groundwork for future mechanism-based targeted therapeutic development.
 Using a combination of cell biological, biochemical and functional assays, these studies are designed to
elucidate the molecular defects and means of correction of ABCC6-associated disease mutations. This
combination of approaches, including newly developed structural and functional assays, will provide a
comprehensive view of the biosynthetic pathway of the ABCC6 ABC-transporter in both normal and mutant
states. By extension, these studies will inform research on other human ABC-transporters, including those
regulating cholesterol homeostasis and associated with cystic fibrosis, for which active therapeutic
development efforts are ongoing. Thus, these studies will inform current and future PXE research efforts and
studies of human diseases associated with ABC-transporters.

## Key facts

- **NIH application ID:** 9983712
- **Project number:** 5R01GM122091-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** PATRICK H THIBODEAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $310,288
- **Award type:** 5
- **Project period:** 2017-09-19 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983712

## Citation

> US National Institutes of Health, RePORTER application 9983712, Altered biosynthesis and function of ABCC6 in systemic mineralization disorders (5R01GM122091-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983712. Licensed CC0.

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