Verdonschot, JAJ;
Vanhoutte, EK;
Claes, GRF;
van den Enden, ATJMH;
Hoeijmakers, JGJ;
Hellebrekers, DMEI;
Haan, AD;
... Brunner, HG; + view all
(2020)
A mutation update for the FLNC gene in myopathies and cardiomyopathies.
Human Mutation
10.1002/humu.24004.
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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.
| Type: | Article |
|---|---|
| Title: | A mutation update for the FLNC gene in myopathies and cardiomyopathies |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/humu.24004 |
| Publisher version: | https://doi.org/10.1002/humu.24004 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, cardiomyopathy, filamin, FLNC, genotype-phenotype correlation, myopathy, ACTIN-BINDING DOMAIN, FILAMIN-C, MYOFIBRILLAR MYOPATHY, HYPERTROPHIC CARDIOMYOPATHY, TRUNCATING VARIANTS, PROTEIN AGGREGATION, MUSCULAR-DYSTROPHY, HEART-FAILURE, CLASSIFICATION, IDENTIFICATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10094770 |
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