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Lookup NU author(s): Dr Andreas Roos, Dr Hadil Alrohaif, Dr Rita Barresi, Dr Ana TopfORCiD, Dr Teresinha Evangelista, Professor Hanns Lochmuller
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© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.
Author(s): Roos A, van der Ven PFM, Alrohaif H, Kolbel H, Heil L, Della Marina A, Weis J, Assent M, Beck-Wodl S, Barresi R, Topf A, O'Connor K, Sickmann A, Kohlschmidt N, El Gizouli M, Meyer N, Daya N, Grande V, Bois K, Kaiser FJ, Vorgerd M, Schroder C, Schara-Schmidt U, Gangfuss A, Evangelista T, Robisch L, Hentschel A, Gruneboom A, Fuerst DO, Kuechler A, Tzschach A, Depienne C, Lochmuller H
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2023
Volume: 146
Issue: 10
Pages: 4200-4216
Print publication date: 01/10/2023
Online publication date: 10/05/2023
Acceptance date: 11/04/2023
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awad152
DOI: 10.1093/brain/awad152
PubMed id: 37163662
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