AI Article Synopsis

  • FILIP1 is a structural protein that plays a role in the function and integrity of neurons and muscles, and mutations in this protein lead to serious health issues, particularly neurological and muscular disorders.
  • Researchers studied five patients from unrelated families who had harmful FILIP1 mutations and found they exhibited a range of symptoms, such as brain malformations and muscle weakness.
  • The findings indicate that defective FILIP1 causes a recessive disorder with both neurological and muscular effects, highlighting issues like protein dysregulation and muscle damage typical of a new condition known as FILIP1opathy.

Article Abstract

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545528PMC
http://dx.doi.org/10.1093/brain/awad152DOI Listing

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