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

作     者：Laura Denman Lael M. Yonker Thomas Bernard Kinane Denman Laura;Yonker Lael M.;Kinane Thomas Bernard

作者机构：Pulmonary Division MassGeneral Hospital for Children Boston MA USA Department of Pediatrics Harvard Medical School Boston MA USA 

出 版 物：《Pediatric Investigation》 (儿科学研究（英文）)

年 卷 期：2018年第2卷第1期

页      面：17-24页

学科分类：1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：chILD Foundation 

主　　题：ATP-binding cassette transporter subfamily A Cystic fibrosis Genetics Interstitial lung diseases Newborn Respiratory distress syndrome 

摘      要：Importance: The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a vital role in surfactant homeostasis. Mutations in the ABCA3 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. ABCA3 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 ABCA3 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 ABCA3 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 ABCA3 mutations. Results: Although the proteins share the same overall structure, only a 19％identity was established between CFTR and ABCA3. The CFTR therapeutic target region has a 22％ homology with the corresponding ABCA3 region. Totally 233 unique protein mutations were identified. All protein mutations were classified and mapped to a schematic diagram of the ABCA3 protein. Interpretation: This new classification system for ABCA3, 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 ABCA3 mutations.