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首页> 外文期刊>British Journal of Haematology >The functional significance of E277K and V295A HFE mutations
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The functional significance of E277K and V295A HFE mutations

机译：E277K和V295A HFE突变的功能意义

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摘要

Hereditary haemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal iron absorption resulting in increased pathological body iron stores. It is typically associated with homozygosity for the c.845G>A (p.C282Y) mutation in the HFE gene. However, other HFE alterations have been reported in affected individuals but their association with the disease is unclear. This study analysed the functional consequences of two HFE mutations, c.829G>A (p.E277K) and c.884T>C (p.V295A). Firstly, it was shown that c.829G>A affects the HFE splicing by diminishing the full length HFE and ivs4_66bp inclusion transcript levels, while increasing the amount of exon 4 skipping transcript. Immunofluorescent techniques showed that the HFE_E277K protein had a diffuse distribution (similar to HFE_C282Y) while HFE_V295A presented at the cell surface and perinuclear compartments (resembling HFE_wt). Immunoprecipitation assays revealed a decreased association of HFE_E277K and HFE_V295A with both β2-microglobulin (B2M; 38 ± 7% and 66 ± 8%, respectively) and transferrin receptor (TFRC, also termed TFR1) (58 ± 2% and 49 ± 16%, respectively). Herein, we prove that both mutations partially abrogate HFE association with B2M and TFRC, crucial for its correct processing and cell surface presentation. Although E277K has a more deleterious effect than V295A, we propose that both mutations may play a role in the development of hereditary haemochromatosis.
机译：遗传性血色素沉着病（HH）是一种常染色体隐性遗传疾病，其特征在于肠道铁的过度吸收，导致病理性体内铁的存储增加。它通常与HFE基因中c.845G> A（p.C282Y）突变的纯合性相关。但是，在受影响的个体中也有其他HFE改变的报道，但是它们与疾病的关联尚不清楚。这项研究分析了两个HFE突变的功能后果，即c.829G> A（p.E277K）和c.884T> C（p.V295A）。首先，表明c.829G> A通过减少全长HFE和ivs4_66bp包含物转录物水平，同时增加外显子4跳过转录物的量来影响HFE剪接。免疫荧光技术表明，HFE_E277K蛋白具有扩散分布（类似于HFE_C282Y），而HFE_V295A存在于细胞表面和核周区室（类似于HFE_wt）。免疫沉淀测定显示HFE_E277K和HFE_V295A与β2-微球蛋白（B2M;分别为38±7％和66±8％）和转铁蛋白受体（TFRC，也称为TFR1）（58±2％和49±16％）的结合减少， 分别）。在本文中，我们证明了这两个突变都部分消除了HFE与B2M和TFRC的关联，这对其正确的加工和细胞表面呈递至关重要。尽管E277K比V295A具有更有害的作用，但我们建议这两个突变都可能在遗传性血色素沉着病的发展中起作用。

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