The classification of ATP ‐binding cassette subfamily A member 3 mutations using the cystic fibrosis transmembrane conductance regulator classification system

Abstract Importance The ATP ‐binding cassette subfamily A member 3 ( ABCA 3) protein plays a vital role in surfactant homeostasis. Mutations in the ABCA 3 gene lead to the development of interstitial lung disease. In the most severe manifestation, mutations can lead to a fatal respiratory distress syndrome in neonates. ABCA 3 belongs to the same ATP ‐binding cassette transporter superfamily as the cystic fibrosis transmembrane conductance regulator ( CFTR ), the gene that causes cystic fibrosis. Objective To classify ABCA 3 mutations in a manner similar to CFTR mutations in order to take advantage of recent advances in therapeutics. Methods Sequence homology between the CFTR protein and the ABCA 3 protein was established. The region of CFTR that is a target for the new potentiator class of drugs was of particular interest. We performed a literature search to obtain all published mutations that were thought to be disease causing. We classified these mutations using the established CFTR classification system. When possible, we drew on previous experimental classification of ABCA 3 mutations. Results Although the proteins share the same overall structure, only a 19% identity was established between CFTR and ABCA 3. The CFTR therapeutic target region has a 22% homology with the corresponding ABCA 3 region. Totally 233 unique protein mutations were identified. All protein mutations were classified and mapped to a schematic diagram of the ABCA 3 protein. Interpretation This new classification system for ABCA 3, based on CFTR classification, will likely aid further research of clinical outcomes and identification of mutation‐tailored therapeutics, with the aim for improving clinical care for patients with ABCA 3 mutations.