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

Hum Mutat. 2021 Jan;42(1):66-76. 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

Affiliations

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

PMID: 33131106 DOI: 10.1002/humu.24130

Abstract

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.

Keywords

CELF2; autistic features; de novo variant; developmental and epileptic encephalopathy; hypotonia.

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