De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy,Human Mutation

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De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy
Human Mutation ( IF 3.3 ) Pub Date : 2020-11-01 , DOI: 10.1002/humu.24130
Toshiyuki Itai ₁ , Kohei Hamanaka ₁ , Kazunori Sasaki ₂ , Matias Wagner _{3,

4} , Urania Kotzaeridou ₅ , Ines Brösse ₅ , Markus Ries ₅ , Yu Kobayashi ₆ , Jun Tohyama ₆ , Mitsuhiro Kato ₇ , Winnie P Ong ₈ , Hui B Chew ₈ , Kavitha Rethanavelu ₈ , Emmanuelle Ranza ₉ , Xavier Blanc ₉ , Yuri Uchiyama _{1,

10} , Naomi Tsuchida _{1,

10} , Atsushi Fujita ₁ , Yoshiteru Azuma ₁ , Eriko Koshimizu ₁ , Takeshi Mizuguchi ₁ , Atsushi Takata ₁ , Noriko Miyake ₁ , Hidehisa Takahashi ₂ , Etsuko Miyagi ₁₁ , Yoshinori Tsurusaki ₁₂ , Hiroshi Doi ₁₃ , Masataka Taguri ₁₄ , Stylianos E Antonarakis _{9,

15} , Mitsuko Nakashima ₁₆ , Hirotomo Saitsu ₁₆ , Satoko Miyatake _{1,

17} , Naomichi Matsumoto ₁

Affiliation

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany.
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital, Niigata, Niigata, Japan.
Department of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, Kuala Lumpur, Malaysia.
Swiss Institute of Genomic Medicine, Medigenome, Geneva, Switzerland.
Rare Disease Genomics Department, Yokohama City University Hospital, Yokohama, Kanagawa, Japan.
Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Faculty of Nutritional Science, Sagami Women's University, Sagamihara, Kanagawa, Japan.
Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Department of Data Science, Yokohama City University School of Data Science, Yokohama, Kanagawa, Japan.
Department of Genetic Medicine, University of Geneva Medical School, Geneva, Switzerland.
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa, Japan.

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1–4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA‐binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole‐exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense‐mediated mRNA decay (NMD), and one canonical splice site variant, c.272‐1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.

中文翻译：

CELF2 中破坏核定位信号的从头变异导致发育性和癫痫性脑病

我们报告了五个无关个体中的杂合CELF2 (NM_006561.3) 变异：个体 1-4 表现出发育性和癫痫性脑病 (DEE)，个体 5 具有智力障碍和自闭症特征。CELF2编码一种核质穿梭 RNA 结合蛋白，该蛋白在 RNA 加工中具有多种作用，并参与中枢神经系统和心脏的胚胎发育。全外显子组测序鉴定出以下CELF2变体：两个错义变体 [c.1558C>T:p.(Pro520Ser) 在不相关的个体 1 和 2 中，以及 c.1516C>G:p.(Arg506Gly) 在个体 3]，个体 4 中的一个移码变体去除了CELF2 c.1562dup:p.(Tyr521Ter) 的最后一个氨基酸，可能导致从无义介导的 mRNA 衰变 (NMD) 中逃脱，以及个体 5 中的一个典型剪接位点变体 c.272-1G>C，也可能导致到 NMD。个体 1、2、4 和 5 中鉴定的变异是从头发现的，而个体 3 中的变异是从她的马赛克母亲那里遗传的。值得注意的是，除 c.272-1G>C 外，所有已识别的变体都聚集在 C 末端的 20 个氨基酸残基内，这可能是核定位信号。互补DNA质粒。我们的研究结果表明，破坏其核定位的CELF2变体与 DEE 相关。

更新日期：2020-12-26

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