Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer
Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer
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WDR77 种系突变易患家族性乳头状甲状腺癌
DOI：
10.1073/pnas.2026327118
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发表时间：
2021-08-03
影响因子：
11.1
通讯作者：
Zhu，Xiaoquan
中科院分区：
文献类型：
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作者：
Zhao，Yanyang;Yu，Tian;Zhu，Xiaoquan
家族性非髓样甲状腺癌(FNMTC)占所有甲状腺肿瘤的15%。在这里，我们报告了两个与NMTC无关的家系中的WDR77基因的生殖线功能缺失变体。WDR77在多种人体组织中都有表达。它与精氨酸甲基转移酶PRMT5蛋白形成复合体，并在青蛙和哺乳动物中介导H4R3me2。功能分析表明，WDR77变异损害了WDR77-PRMT5复合体的形成，导致患者H4R3me2减少。WDR77基因的敲除会促进甲状腺癌细胞的生长。综上所述，我们的发现揭示了FNMTC的易感基因，并扩大了FNMTC的易感变异谱。此外，这份报告还介绍了与人类疾病相关的WDR77的生殖系变异。非综合征家族性非髓样甲状腺癌(FNMTC)的遗传易感性尚不清楚。在这里，我们报告了两个不相关的非综合征FNMTC家族中的六个人患有乳头状甲状腺癌(PTC)。全外显子组测序显示，WDR77的28个碱基片段中存在两个胚系功能丧失变体，该片段编码与精氨酸甲基转移酶PRMT5蛋白形成的转甲基酶复合体的核心成员，该蛋白负责青蛙和哺乳动物中的组蛋白H4精氨酸3二甲基化(H4R3me2)。到目前为止，WDR77与人类癌症易感性之间的联系尚不清楚。在WDR77外显子6中发现一种罕见的杂合性错义突变(R198H)，该突变发生在一个三口之家。内含子6 5‘端的杂合性剪接点突变(c.619+1G>；C)存在于另一个家系的3个患病成员中。R198H突变体削弱了WDR77与PRMT5的相互作用，剪接点突变导致外显子6跳过，导致突变信使RNA显著减少，同时突变携带者中H4R3me2水平明显降低。WDR77基因的敲除会促进甲状腺癌细胞的生长。对WDR77突变患者甲状腺组织的全转录组分析显示，在促进细胞周期和抑制细胞凋亡的过程中，丰富的途径发生了变化。综上所述，我们报告了WDR77突变使患者易患非综合征家族性PTC，并将胚系WDR77变异与人类恶性疾病联系起来。
Significance Familial nonmedullary thyroid cancer (FNMTC) accounts for up to 15% of all thyroid tumors. Here, we report two germ-line loss-of-function variants in WDR77 in two unrelated families with NMTC. WDR77 is expressed in diverse human tissues. It forms a complex with the protein arginine methyltransferase PRMT5 and mediates H4R3me2 in frogs and mammals. Functional analyses show that WDR77 variants impair formation of the complex of WDR77–PRMT5, resulting in reduced H4R3me2 in patients. Knockdown of WDR77 results in increased growth of thyroid cancer cells. Taken together, our findings reveal a predisposing gene of FNMTC and expand the variant profile predisposing to FNMTC. Additionally, this report presents germ-line variants in WDR77 associated with human disease. The inheritance of predisposition to nonsyndromic familial nonmedullary thyroid cancer (FNMTC) remains unclear. Here, we report six individuals with papillary thyroid cancer (PTC) in two unrelated nonsyndromic FNMTC families. Whole-exome sequencing revealed two germ-line loss-of-function variants occurring within a 28-bp fragment of WDR77, which encodes a core member of a transmethylase complex formed with the protein arginine methyltransferase PRMT5 that is responsible for histone H4 arginine 3 dimethylation (H4R3me2) in frogs and mammals. To date, the association of WDR77 with susceptibility to cancer in humans is unknown. A very rare heterozygous missense mutation (R198H) in WDR77 exon 6 was identified in one family of three affected siblings. A heterozygous splice-site mutation (c.619+1G > C) at the 5′ end of intron 6 is present in three affected members from another family. The R198H variant impairs the interaction of WDR77 with PRMT5, and the splice-site mutation causes exon 6 skipping and results in a marked decrease in mutant messenger RNA, accompanied by obviously reduced H4R3me2 levels in mutation carriers. Knockdown of WDR77 results in increased growth of thyroid cancer cells. Whole-transcriptome analysis of WDR77 mutant patient-derived thyroid tissue showed changes in pathways enriched in the processes of cell cycle promotion and apoptosis inhibition. In summary, we report WDR77 mutations predisposing patients to nonsyndromic familial PTC and link germ-line WDR77 variants to human malignant disease.