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Open AccessArticle

The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates De Novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation

1
Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
2
Department of Biochemistry, Jichi Medical University, Shimotsuke, Tochigi 321-0498, Japan
3
Laboratory of Bioengineering, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
4
Tsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan
5
Laboratory of Molecular Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: William Cho
Received: 27 November 2020 / Revised: 19 January 2021 / Accepted: 26 January 2021 / Published: 1 February 2021
(This article belongs to the Section Neurology and Neurologic Diseases)
Background: Genetic hypomyelinating diseases are a heterogeneous group of disorders involving the white matter. One infantile hypomyelinating leukoencephalopathy is associated with the homozygous variant (Cys4-to-Ser (C4S)) of the c11orf73 gene. Methods: We observed that in mouse oligodendroglial FBD-102b cells, the C4S mutant proteins but not the wild type ones of C11orf73 are microscopically localized in the lysosome. And, they downregulate lysosome-related signaling in an immunoblotting technique. Results: The C4S mutant proteins specifically interact with Filamin A, which is known to anchor transmembrane proteins to the actin cytoskeleton; the C4S mutant proteins and Filamin A are also observed in the lysosome fraction. While parental FBD-102b cells and cells harboring the wild type constructs exhibit morphological differentiation, cells harboring C4S mutant constructs do not. It may be that morphological differentiation is inhibited because expression of these C4S mutant proteins leads to defects in the actin cytoskeletal network involving Filamin A. Conclusions: The findings that leukoencephalopathy-associated C11ORF73 mutant proteins specifically interact with Filamin A, are localized in the lysosome, and inhibit morphological differentiation shed light on the molecular and cellular pathological mechanisms that underlie infantile hypomyelinating leukoencephalopathy. View Full-Text
Keywords: leukoencephalopathy; HLD13; C11orf73; Filamin A; oligodendrocyte differentiation leukoencephalopathy; HLD13; C11orf73; Filamin A; oligodendrocyte differentiation
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MDPI and ACS Style

Hattori, K.; Tago, K.; Memezawa, S.; Ochiai, A.; Sawaguchi, S.; Kato, Y.; Sato, T.; Tomizuka, K.; Ooizumi, H.; Ohbuchi, K.; Mizoguchi, K.; Miyamoto, Y.; Yamauchi, J. The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates De Novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation. Medicines 2021, 8, 9. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines8020009

AMA Style

Hattori K, Tago K, Memezawa S, Ochiai A, Sawaguchi S, Kato Y, Sato T, Tomizuka K, Ooizumi H, Ohbuchi K, Mizoguchi K, Miyamoto Y, Yamauchi J. The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates De Novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation. Medicines. 2021; 8(2):9. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines8020009

Chicago/Turabian Style

Hattori, Kohei; Tago, Kenji; Memezawa, Shiori; Ochiai, Arisa; Sawaguchi, Sui; Kato, Yukino; Sato, Takanari; Tomizuka, Kazuma; Ooizumi, Hiroaki; Ohbuchi, Katsuya; Mizoguchi, Kazushige; Miyamoto, Yuki; Yamauchi, Junji. 2021. "The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates De Novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation" Medicines 8, no. 2: 9. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines8020009

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