气候变化领域集成服务门户(CCPortal): Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer

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DOI	10.1073/pnas.2026327118
	Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer
	Zhao Y.; Yu T.; Sun J.; Wang F.; Cheng C.; He S.; Chen L.; Xie D.; Fu L.; Guan X.; Yan A.; Li Y.; Miao G.; Zhu X.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Familial papillary thyroid cancer; Germ-line mutations; Predisposition; WDR77
语种	英语
scopus关键词	messenger RNA; transcription factor; WDR77 protein, human; adult; amino acid sequence; female; gene expression regulation; genetic predisposition; genetics; germline mutation; human; male; metabolism; middle aged; missense mutation; molecular model; mutation; pathology; protein conformation; thyroid gland; thyroid tumor; whole exome sequencing; Adult; Amino Acid Sequence; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Middle Aged; Models, Molecular; Mutation; Mutation, Missense; Protein Conformation; RNA, Messenger; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Transcription Factors; Whole Exome Sequencing
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251093
作者单位	Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Beijing, 100730, China; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China; Department of General Surgery, Beijing Hospital, National Health Commission, Beijing, 100730, China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China; Department of Ultrasonography, Beijing Hospital, National Health Commission, Beijing, 100730, China; Research and Development, Mingma Technologies Co., Ltd., Shanghai, 200131, China; Department of Pathology, Beijing Hospital, National Health Commission, Beijing, 100730, China
推荐引用方式 GB/T 7714	Zhao Y.,Yu T.,Sun J.,et al. Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer[J],2021,118(31).
APA	Zhao Y..,Yu T..,Sun J..,Wang F..,Cheng C..,...&Zhu X..(2021).Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Zhao Y.,et al."Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).