Dataset Information

Bi-allelic variants of FILIP1 cause a congenital syndrome defined by facial dysmorphisms and a broad range of neurological manifestations

ABSTRACT: Filamin-A-interacting protein 1 (FILIP1) is a structural protein known to take on roles in neuronal and muscle function and integrity and to interact in addition to filamin-A with filamin-C. For both proteins pathogenic variants in the corresponding genes were linked to neurological symptoms and dysmorphisms (FLNA) or muscular diseases (FLNC) characterized by myofibrillar perturbations. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense) leading to a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay as well as muscle weakness and pathology complicated by dysmorphic features shared among patients. Microscopic studies on the muscle biopsy derived from one patient harbouring a missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc thus introducing FILIP1 as a novel candidate gene of myofibrillar myopathies. Further functional studies confirmed the altered stability of this p.[Pro1133Leu] missense-mutant FILIP1 protein. Proteomic studies on the fibroblasts derived from the same patient revealed a dysregulation of a variety of proteins including FLNc, a biochemical finding which might accord with the manifestation of certain symptoms associated with the syndromic phenotype of FILIP1opathy.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin Fibroblast

SUBMITTER: Andreas Hentschel

LAB HEAD: Dr. Andreas Hentschel

PROVIDER: PXD036407 | Pride | 2024-05-23

REPOSITORIES: Pride

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Bi-allelic variants of FILIP1 cause congenital myopathy, dysmorphism and neurological defects.

Roos Andreas A van der Ven Peter F M PFM Alrohaif Hadil H Kölbel Heike H Heil Lorena L Della Marina Adela A Weis Joachim J Aßent Marvin M Beck-Wödl Stefanie S Barresi Rita R Töpf Ana A O'Connor Kaela K Sickmann Albert A Kohlschmidt Nicolai N El Gizouli Magdeldin M Meyer Nancy N Daya Nassam N Grande Valentina V Bois Karin K Kaiser Frank J FJ Vorgerd Matthias M Schröder Christopher C Schara-Schmidt Ulrike U Gangfuss Andrea A Evangelista Teresinha T Röbisch Luisa L Hentschel Andreas A Grüneboom Anika A Fuerst Dieter O DO Kuechler Alma A Tzschach Andreas A Depienne Christel C Lochmüller Hanns H

Brain : a journal of neurology 20231001 10

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 homozygo ...[more]

PMID: 37163662

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Project description:The elucidation of pathomechanisms leading to the manifestation of neuromuscular diseases (NMDs) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial especially regarding the fact that muscle and nerve biopsies became less common in the diagnostic work-up of patients suffering from NMDs. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. To systematically address the question if human skin fibroblasts might serve as a valuable biomaterial for (molecular) studies of NMDs, using proteomic profiling we generated a protein library by decreasing protein complexity via pH8-based sample fractionation: cataloguing of 8280 proteins revealed the expression of a variety of such linked to genetic forms of motor neuron diseases, congenital myasthenic syndromes, neuropathies and muscular disorders. In silico-based pathway analyses revealed expression of a variety of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMDs. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMDs by a use case: utilizing a data independent acquisition (DIA) approach, the proteomic signature of whole protein extracts of fibroblasts derived from an Allgrove-patient was studied. Paradigmatic dysregulated proteins were confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, LC-MS/MS-based investigation of nuclear protein composition allowed the identification of protein-dysregulations which accord with structural perturbations observed in the muscle biopsy.

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	F007630.dat	Other
	Velos02_15072.raw	Raw
	Velos02_15073.raw	Raw
	Velos02_15074.raw	Raw
	Velos02_15079.raw	Raw