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De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy
Author(s) -
Itai Toshiyuki,
Hamanaka Kohei,
Sasaki Kazunori,
Wagner Matias,
Kotzaeridou Urania,
Brösse Ines,
Ries Markus,
Kobayashi Yu,
Tohyama Jun,
Kato Mitsuhiro,
Ong Winnie P.,
Chew Hui B.,
Rethanavelu Kavitha,
Ranza Emmanuelle,
Blanc Xavier,
Uchiyama Yuri,
Tsuchida Naomi,
Fujita Atsushi,
Azuma Yoshiteru,
Koshimizu Eriko,
Mizuguchi Takeshi,
Takata Atsushi,
Miyake Noriko,
Takahashi Hidehisa,
Miyagi Etsuko,
Tsurusaki Yoshinori,
Doi Hiroshi,
Taguri Masataka,
Antonarakis Stylianos E.,
Nakashima Mitsuko,
Saitsu Hirotomo,
Miyatake Satoko,
Matsumoto Naomichi
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24130
Subject(s) - biology , frameshift mutation , genetics , missense mutation , nonsense mediated decay , nuclear localization sequence , exome sequencing , rna splicing , rna , mutation , gene
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.