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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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Project description:Background. COVID-19-induced neurological disease is a growing concern. Here we provide a comprehensive clinical, molecular, and neuroimaging investigation of patients presenting neurological symptoms to investigate underlying processes. Methods. We performed a detailed systematized clinical, laboratory, and neuroimaging (CT/MRI) data analysis from 35 mild to severe Brazilian COVID-19 hospitalised patients with clinical indications for cerebrospinal fluid (CSF) exam. In patients' CSF, we measured interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and the Alzheimer's disease-associated biomarkers amyloid-beta (Aβ)1-40, Aβ1-42, Tau and pTau181 levels (n=31-35). In addition, CSF proteomics and the search for SARS-CoV-2 spike protein presence using shotgun and targeted multiple reaction monitoring liquid-chromatography/mass-spectrometry were performed (n=16). We further evaluated a 29-cytokine panel in patients’ blood (n=16). An electronic questionnaire was conducted one-year post-hospitalisation (n=19, 63.3%). Findings. COVID-19 patients presented heterogeneous clinical and neurological features, including encephalopathy, encephalitis, and neuromuscular syndromes, despite low pulmonary burden. Patients showed increased circulating cytokines and CSF IL-6 and TNF-α levels compared to controls. Alzheimer’s disease-related biomarkers were unaltered compared to controls. COVID-19 altered CSF proteomic pathways associated to complement and coagulation cascades, immune-inflammatory, metabolism and amyloidosis. We found no traces of spike protein in patients’ CSF. Severe patients presented more pronounced neuroimaging alterations, altered CSF levels of IL-6, Tau, and Aβ-species compared to mild patients. Peripheral inflammation markers correlated with CSF IL-6 and Tau-species levels. Finally, in a one-year post-COVID survey, survivors were not recovered entirely (12/19) and reported confusion or memory/attention deficits (13/19). Interpretation. COVID-19 induces a broad spectrum of neurological presentations associated with changes in central nervous system (CNS) inflammatory and neurodegenerative molecular and structural biomarkers that correlate with systemic inflammation and disease severity. Given that neurological symptoms persist up to one-year post-COVID, our results urge us to investigate whether systemic, and CNS molecular changes are permanent or alleviated so that COVID-19 patients with lingering symptoms are adequately treated.

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

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