Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss
Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss
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DOI：
10.1016/j.ebiom.2020.102810
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发表时间：
2020-07-01
期刊：
影响因子：
11.1
通讯作者：
Ikeda, Shigaku
中科院分区：
文献类型：
--
作者：
Oka, Akira;Takagi, Atsushi;Ikeda, Shigaku
背景：斑秃（AA）被认为是一种高度遗传的、T细胞介导的毛囊自身免疫性疾病。然而，没有令人信服的易感基因尚未被查明的主要组织相容性复合体（MHC），基因组区域已知与AA相比，其他regions.Methods：我们设计的小鼠携带AA风险等位基因通过单倍型测序的MHC区域使用等位基因特异性基因组编辑与CRISPR/Cas9系统。最后，我们进行了功能评估的小鼠和AA患者和没有的风险allelocate.Findings：我们确定了一个变体（rs 142986308，p.Arg587Trp）的卷曲螺旋α-螺旋杆蛋白1（CCHCR 1）基因作为唯一的非同义变异的AA风险单倍型。此外，基因改造后携带风险等位基因的小鼠表现出脱发表型。转录组学进一步确定CCHCR 1作为一种新的组件与毛干中的毛皮质角蛋白相互作用。这两个，这些alopecic小鼠和AA患者的风险等位基因显示形态受损的头发和头发相关基因，包括头发角蛋白和角蛋白相关蛋白（KRTAPs）的差异表达，解释：我们的研究结果牵连CCHCR 1与风险等位基因在一个以前未确定的AA亚型的基础上异常角化除了自身免疫事件。
Background: Alopecia areata (AA) is considered a highly heritable, T-cell-mediated autoimmune disease of the hair follicle. However, no convincing susceptibility gene has yet been pinpointed in the major histocompatibility complex (MHC), a genome region known to be associated with AA as compared to other regions.Methods: We engineered mice carrying AA risk allele identified by haplotype sequencing for the MHC region using allele-specific genome editing with the CRISPR/Cas9 system. Finally, we performed functional evaluations in the mice and AA patients with and without the risk allele.Findings: We identified a variant (rs142986308, p.Arg587Trp) in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene as the only non-synonymous variant in the AA risk haplotype. Furthermore, mice engineered to carry the risk allele displayed a hair loss phenotype. Transcriptomics further identified CCHCR1 as a novel component interacting with hair cortex keratin in hair shafts. Both, these alopecic mice and AA patients with the risk allele displayed morphologically impaired hair and comparable differential expression of hairrelated genes, including hair keratin and keratin-associated proteins (KRTAPs).Interpretation: Our results implicate CCHCR1 with the risk allele in a previously unidentified subtype of AA based on aberrant keratinization in addition to autoimmune events.