Identification of a Novel Heterozygous Mutation in the EIF2B4 Gene Associated With Vanishing White Matter Disease

Yun Tian; Qiong Liu; Yafang Zhou; Xiao-Yu Chen; Yongcheng Pan; Hongwei Xu; Zhuanyi Yang

doi:10.3389/fbioe.2022.901452

Identification of a Novel Heterozygous Mutation in the EIF2B4 Gene Associated With Vanishing White Matter Disease

Front Bioeng Biotechnol. 2022 Jul 4:10:901452. doi: 10.3389/fbioe.2022.901452. eCollection 2022.

Authors

Yun Tian^{1

2}, Qiong Liu^{3

4}, Yafang Zhou^{1

2}, Xiao-Yu Chen⁵, Yongcheng Pan^{3

4}, Hongwei Xu^{1

2}, Zhuanyi Yang⁵

Affiliations

¹ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
⁵ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Vanishing white matter disease (VWM) is one of the most common childhood inherited leukoencephalopathies with autosomal recessive inheritance. Mutations in five genes, EIF2B1-5, have been identified as the major cause of VWM. In this study, a targeted gene capture sequencing panel comprising 160 known pathogenic genes associated with leukoencephalopathies was performed in a large Han Chinese family affected by adult-onset VWM, and a novel heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 (NM_001034116.2) was detected. Further functional studies in HEK 293 cells showed dramatically reduced EIF2Bδ protein levels in the mutated group compared with the wild-type group. This study revealed that a heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 was potentially associated with the adult-onset mild phenotype of VWM. In contrast to previous reports, autosomal dominant inheritance was also observed in adult-onset VWM.

Keywords: EIF2B4; heterozygous missense mutation; loss of function; targeted gene capture sequencing panel; vanishing white matter disease.