Year: 2020
Type: review
Abstract: Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.
Source: Human Mutation
DOI: 10.1002/humu.24004
Authors: Job A. J. Verdonschot, Els K. Vanhoutte, Godelieve R. F. Claes, Apollonia T. J. M. Helderman‐van den Enden, Janneke G. J. Hoeijmakers, Debby M. E. I. Hellebrekers, Amber Haan, Imke Christiaans, Ronald H. Lekanne Deprez, Hanne M. Boen, Emeline M. Craenenbroeck, Bart L. Loeys, Yvonne M. Hoedemaekers, Carlo Marcelis, Marlies Kempers, Esther Brusse, Jaap I. Waning, Annette F. Baas, Dennis Dooijes, Folkert W. Asselbergs, Daniela Q. C. M. Barge‐Schaapveld, Pieter Koopman, Arthur Wijngaard, Stephane R. B. Heymans, Ingrid P. C. Krapels, Han G. Brunner
Institutions: Maastricht University Medical Centre, University Medical Center Groningen, Amsterdam University Medical Centers, University of Antwerp, Antwerp University Hospital, Radboud University Nijmegen, Radboud University Medical Center, Erasmus MC, University Medical Center Utrecht, Leiden University Medical Center, Hartcentrum Hasselt, Netherlands Heart Institute, KU Leuven
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
OpenAlex ID: W3007179165