PD Dr.rer nat Andreas Roos (Essen / DE), Dr. Peter van der Ven (Bonn / DE), PD Dr. med Heike Kölbel (Essen / DE), Dr. med. Adela Della Marina (Essen / DE), Univ.-Prof. Dr. med. Joachim Weis (Aachen / DE), Dr. Stefanie Beck-Wödl (Tübingen / DE), Prof. Dr. Frank J. Kaiser (Essen / DE), Prof. Dr. Matthias Vorgerd (Bochum / DE), Prof. Dr. med Ulrike Schara-Schmidt (Essen / DE), Dr. med. Andrea Gangfuß (Essen / DE), Dr. Andreas Hentschel (Dortmund / DE), Prof. Dr. Anika Grüneboom (Dortmund / DE), Prof. Dr. Dieter Fuerst (Bonn / DE), PD Dr. Alma Küchler (Essen / DE), Prof. Dr. Andreas Tzschach (Freiburg / DE), Prof. Dr. Christel Depienne (Essen / DE), Prof. Dr. med. Hanns Lochmüller (Ottawa, ON / CA)
Abstract-Text (inkl. Referenzen)
Introduction:
Filamin-A-interacting protein 1 (FILIP1) is a structural protein involved in neuronal and muscle function and integrity and is interacting with FLNa and FLNc. Although for FLNA and FLNC pathogenic variants were linked to neurological diseases, no phenotype was linked to FILIP1 variants thus far.
Materials and Methods:
Exome sequencing was carried out in five patients from four consanguineous families presenting with congenital myopathy, intellectual disability and facial dysmorphisms. Muscle pathology was studied by histology and electron microscopy. In vitro studies (including proteomics, ELISA and immunofluorescence) were carried out on fibroblasts and in bacteria to investigate the etiopathology.
Results:
Two nonsense and two missense variants affecting FILIP1 were identified, respectively. Muscle pathology includes sarcomeric disintegration. Functional studies indicated altered stability of missense mutant FILIP1 and display a reduced cellular viability along with a widespread effect on cytoskeleton also characterized by dysregulation of FLNa and FLNc.
Conclusions:
Our combined results introduce FILIP1 as a novel gene for congenital myopathies and provide the first insights into the underlying pathophysiology.