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

Ann Neurol. 2018 Apr;83(4):794-806. doi: 10.1002/ana.25208.

Mitsuko Nakashima ¹ ², Mitsuhiro Kato ³ ⁴, Kazushi Aoto ², Masaaki Shiina ⁵, Hazrat Belal ², Souichi Mukaida ⁶, Satoko Kumada ⁷, Atsushi Sato ⁷ ⁸, Ayelet Zerem ⁹, Tally Lerman-Sagie ⁹, Dorit Lev ¹⁰, Huey Yin Leong ¹¹, Yoshinori Tsurusaki ¹, Takeshi Mizuguchi ¹, Satoko Miyatake ¹, Noriko Miyake ¹, Kazuhiro Ogata ⁵, Hirotomo Saitsu ², Naomichi Matsumoto ¹

Affiliations

1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
2 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
3 Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
4 Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
5 Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
6 Department of Pediatric Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan.
7 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
8 Department of Pediatrics, The University of Tokyo Hospital, Tokyo, Japan.
9 Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Sackler School of Medicine, Tel-Aviv University, Tel- Aviv, Israel.
10 Institute of Medical Genetics, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Sackler School of Medicine, Tel-Aviv University, Tel- Aviv.
11 Genetic Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.

PMID: 29534297 DOI: 10.1002/ana.25208

Abstract

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.

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