RT Journal Article
SR Electronic
T1 <em>De novo EIF2AK1</em> and <em>EIF2AK2</em> variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 757039
DO 10.1101/757039
A1 Dongxue Mao
A1 Chloe M. Reuter
A1 Maura R.Z. Ruzhnikov
A1 Anita E. Beck
A1 Emily G. Farrow
A1 Lisa T. Emrick
A1 Jill A. Rosenfeld
A1 Katherine M. Mackenzie
A1 Laurie Robak
A1 Matthew T. Wheeler
A1 Lindsay C. Burrage
A1 Mahim Jain
A1 Pengfei Liu
A1 Daniel Calame
A1 Sebastien Küry
A1 Martin Sillesen
A1 Klaus Schmitz-Abe
A1 Davide Tonduti
A1 Luigina Spaccini
A1 Maria Iascone
A1 Casie A. Genetti
A1 Madeline Graf
A1 Alyssa Tran
A1 Mercedes Alejandro
A1 Undiagnosed Diseases Network
A1 Brendan H. Lee
A1 Isabelle Thiffault
A1 Pankaj B. Agrawal
A1 Jonathan A. Bernstein
A1 Hugo J. Bellen
A1 Hsiao-Tuan Chao
YR 2019
UL http://biorxiv.org/content/early/2019/09/16/757039.abstract
AB EIF2AK1 and EIF2AK2 encode members of the Eukaryotic Translation Initiation Factor 2 Alpha Kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of eight unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/8) or EIF2AK2 (7/8). Features seen in these eight individuals include white matter alterations (8/8), developmental delay (8/8), impaired language (8/8), cognitive impairment (7/8), ataxia (6/8), dysarthria in probands with verbal ability (6/6), hypotonia (6/8), hypertonia (5/8), and involuntary movements (3/8). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and patient-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate Eukaryotic Translation Initiation Factor 2 Subunit 1, (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), a leukoencephalopathy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.