Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients
Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients
复制标题
DOI：
10.1093/hmg/ddu160
复制
发表时间：
2014-09-01
影响因子：
3.5
通讯作者：
Le Gac, Gerald
中科院分区：
文献类型：
--
作者：
Callebaut, Isabelle;Joubrel, Rozenn;Le Gac, Gerald
血色素沉着症4型是一种罕见的原发性铁超载，作为常染色体显性遗传性状，由编码铁转运蛋白ferroportin 1（SLC 40 A1）的基因突变引起。SLC 40 A1突变分为两个功能类别（功能丧失与功能获得），这两个类别是两种不同临床实体（血色素沉着症4A型与4 B型）的基础。然而，绝大多数SLC 40 A1突变是罕见的错义变异，只有少数显示出强有力的因果关系证据。本研究报告了一种综合方法的结果，该方法收集了44名疑似血色素沉着病4型患者的遗传和表型数据，并进行了全面的结构和功能注释。因果关系被证明为10个错义变异，显示了一个明确的二分法之间的两个血色素沉着病4型亚型。两个亚组的功能丧失突变进行了区分：一个损害细胞表面的表达和一个只改变铁的出口。此外，一个新的功能获得性突变被确定，铁调素结合的铁转运蛋白的降解可能取决于铁调素结合结构域外的一个大的细胞外环的完整性。另一方面，8个进一步的错义变异在蛋白质或RNA水平上没有明显的影响;这些都是在明显孤立的患者中发现的，与不太严重的表型相关。目前的研究结果说明了将计算机模拟和生物化学方法相结合以完全区分致病性SLC 40 A1突变与良性变异的重要性。这对患者管理有着深远的影响。
Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss-versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type 4A versus type 4B). However, the vast majority of SLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance of combining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.