A mutation update for the FLNC gene in myopathies and cardiomyopathies.,Human Mutation

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A mutation update for the FLNC gene in myopathies and cardiomyopathies.
Human Mutation ( IF 3.3 ) Pub Date : 2020-03-20 , DOI: 10.1002/humu.24004
Job A J Verdonschot _{1,

2} , Els K Vanhoutte ₁ , Godelieve R F Claes ₁ , Apollonia T J M Helderman-van den Enden ₁ , Janneke G J Hoeijmakers ₃ , Debby M E I Hellebrekers ₁ , Amber de Haan ₁ , Imke Christiaans _{4,

5} , Ronald H Lekanne Deprez ₄ , Hanne M Boen ₆ , Emeline M van Craenenbroeck ₆ , Bart L Loeys ₇ , Yvonne M Hoedemaekers _{5,

8} , Carlo Marcelis ₈ , Marlies Kempers ₈ , Esther Brusse ₉ , Jaap I van Waning _{10,

11} , Annette F Baas ₁₂ , Dennis Dooijes ₁₂ , Folkert W Asselbergs ₁₃ , Daniela Q C M Barge-Schaapveld ₁₄ , Pieter Koopman ₁₅ , Arthur van den Wijngaard ₁ , Stephane R B Heymans _{2,

16,

17} , Ingrid P C Krapels ₁ , Han G Brunner _{1,

8,

18}

Affiliation

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Clinical Genetics, University Medical Centre Groningen, Groningen, The Netherlands.
Department of Cardiology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Department of Clinical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Department of Neurology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.
Department of Cardiology, Heart Center Hasselt, Belgium.
Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
The Netherlands Heart Institute, Utrecht, The Netherlands.
Department of Genetics and Cell Biology, GROW Institute for Developmental Biology and Cancer, Maastricht University Medical Centre, Maastricht, The Netherlands.

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.

中文翻译：

肌病和心肌病中 FLNC 基因的突变更新。

细丝蛋白 C (FLNC) 变体与心脏和肌肉表型相关。最初，在肌原纤维肌病 (MFM) 患者中描述了 FLNC 变异。后来，心肌病队列中的高通量筛选确定了 FLNC 在孤立的肥厚型和扩张型心肌病（HCM 和 DCM）中的重要作用。FLNC 变异现在是遗传性 DCM 的更普遍原因之一。FLNC 相关 DCM 与恶性临床病程和心源性猝死的高风险相关。FLNC 的临床谱表明与变异类型及其在基因中的位置相关的不同病理机制。FLNC 的适当功能对于肌节的结构完整性和细胞信号传导至关重要。FLNC 的二级蛋白质结构对于确保这一功能至关重要。具有后续单倍剂量不足的截断变异与 DCM 和心律失常有关。正如在 HCM 和 MFM 中发现的那样，干扰蛋白质的二聚化和折叠会导致对肌肉功能有害的聚集体形成。与 HCM 相关的变异主要是错义变异，它们聚集在 ROD2 域中。该域对于与肌节结合并确保适当的细胞信号传导很重要。我们在此根据现有证据审查 FLNC 基因型-表型相关性。该域对于与肌节结合并确保适当的细胞信号传导很重要。我们在此根据现有证据审查 FLNC 基因型-表型相关性。该域对于与肌节结合并确保适当的细胞信号传导很重要。我们在此根据现有证据审查 FLNC 基因型-表型相关性。

更新日期：2020-03-20

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