De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy

Mitsuko Nakashima, Mitsuhiro Kato, Kazushi Aoto, Masaaki Shiina, Hazrat Belal, Souichi Mukaida, Satoko Kumada, Atsushi Sato, Ayelet Zerem, Tally Lerman-Sagie, Dorit Lev, Huey Yin Leong, Yoshinori Tsurusaki, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Kazuhiro Ogata, Hirotomo Saitsu*, Naomichi Matsumoto

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway. Methods: We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments. Results: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2. Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794–806.

Original languageEnglish
Pages (from-to)794-806
Number of pages13
JournalAnnals of Neurology
Issue number4
StatePublished - Apr 2018


FundersFunder number
Takeda Science Foundation
Yokohama Foundation for Advanced Medical Science
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science17H01539, 17K08513, 17K19536, 18K19305, 16H03293, 16H05160, 16H05357, 17K15630
Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology Agency
Ministry of Health, Labour and Welfare
Hayashi Memorial Foundation for Female Natural Scientists


    Dive into the research topics of 'De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy'. Together they form a unique fingerprint.

    Cite this