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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1429177
This article is part of the Research Topic Exploring the Key Targets and Compounds That Manipulate Brain Neurocircuits Against Mental Disorders and Psychiatric Volume II View all 9 articles

Unraveling the Pathogenic Mechanism of a Novel Filamin A Frameshift Variant in Periventricular Nodular Heterotopia

Provisionally accepted
Chunran Xue Chunran Xue 1Yishu Wang Yishu Wang 1Jing Peng Jing Peng 1Sisi Feng Sisi Feng 2Yangtai Guan Yangtai Guan 3*Yong Hao Yong Hao 1*
  • 1 Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 2 Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), Shanghai, China
  • 3 Department of Neurology, Punan Branch of Renji Hospital, Shanghai Jiaotong University, Shanghai, China

The final, formatted version of the article will be published soon.

    Background: Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder caused by the inability of neurons to move to the cortex. Patients with PVNH often experience epilepsy due to ectopic neuronal discharges. Most cases of PVNH are associated with variations in filamin A (FLNA), which encodes an actin-binding protein. However, the underlying pathological mechanisms remain unclear. Methods: Next-generation sequencing was performed to detect variants in patients with PVNH, and the findings were confirmed using Sanger sequencing. Iterative threading assembly refinement was used to predict the structures of the variant proteins, and the search tool for the retrieval of interacting genes/proteins database was used to determine the interactions between FLNA and motility-related proteins. An induced pluripotent stem cell (iPSC) line was generated as a disease model by reprogramming human peripheral blood mononuclear cells. The FLNA expression in iPSCs was assessed using western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence analysis was performed to determine the arrangement of F-actin. Results: A novel FLNA frameshift variant (NM_001456.3: c.1466delG, p. G489Afs*9) was identified in a patient with PVNH and epilepsy. Bioinformatic analysis indicated that this variation was likely to impair FLNA function. Western blot and qRT-PCR analysis of iPSCs derived from the patient's peripheral blood mononuclear cells revealed the absence of FLNA protein and mRNA. Immunofluorescence analysis suggested an irregular arrangement and disorganization of F-actin compared to that observed in healthy donors.Our findings indicate that the frameshift variant of FLNA (NM_001456.3: c.1466delG, p. G489Afs*9) impairs the arrangement and organization of F-actin, potentially influencing cell migration and causing PVNH.

    Keywords: filamin A, Periventricular Nodular Heterotopia, Epilepsy, induced pluripotent stem cell, f-actin

    Received: 07 May 2024; Accepted: 13 Sep 2024.

    Copyright: © 2024 Xue, Wang, Peng, Feng, Guan and Hao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yangtai Guan, Department of Neurology, Punan Branch of Renji Hospital, Shanghai Jiaotong University, Shanghai, China
    Yong Hao, Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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