Holtzhausen Christian, Heil Lorena, Klingel Karin, Fox Henrik, Gummert Jan, Gärtner Anna, Schmidt Andreas, Krüger Marcus, Kirfel Gregor, van der Ven Peter F M, Milting Hendrik, Clemen Christoph S, Schröder Rolf, Fürst Dieter O, Tiesmeier Jens
Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
Hum Mol Genet. 2025 Apr 6;34(8):726-738. doi: 10.1093/hmg/ddaf014.
Mutations in the human FLNC gene encoding filamin C (FLNc) cause a broad spectrum of sporadic and familial cardiomyopathies and myopathies. We report on the genetic, clinical, morphological and biochemical findings in a German family harboring an FLNC variant that leads to severe cardiac disease comprising sudden cardiac death and arrhythmogenic cardiomyopathy. Genetic analysis identified a novel heterozygous FLNC variant in exon 16 (NM_001458.4:c.2495_2498delAGTA, het; p.K832TfsX45) in i) the index patient suffering from dilated cardiomyopathy necessitating heart transplantation, ii) a son, who died from sudden cardiac death, iii) a second son, who survived an episode of sudden cardiac arrest and iv) a third son affected by isolated skeletal muscle myopathy. FLNc protein levels were markedly reduced in cardiac tissue obtained from the index patient, implying that the p.K832TfsX45 FLNc variant most probably caused nonsense-mediated decay of the corresponding mRNA. Morphological analysis of the diseased cardiac tissue revealed extensive fibrotic remodeling, and marked degenerative changes of the contractile apparatus of cardiomyocytes and severe structural alterations of intercalated discs. Connexin-43 signal intensity at intercalated discs was diminished and FLNc labelling of myofibrils was attenuated or even absent. Proteome analyses demonstrated complex alterations of extracellular matrix and intercalated disc proteins. Our findings demonstrate that this novel, truncating FLNC mutation likely leads to haploinsufficiency, thereby causing a deleterious sequence of degenerative changes of cardiac tissue with extensive fibrotic remodeling and intercalated disc pathology as the structural basis for FLNC-related cardiomyopathy with life-threatening cardiac arrhythmias.
编码细丝蛋白C（FLNc）的人类FLNC基因突变会导致多种散发性和家族性心肌病及肌病。我们报告了一个德国家庭的基因、临床、形态学和生化研究结果，该家庭携带一种FLNC变体，可导致包括心源性猝死和致心律失常性心肌病在内的严重心脏疾病。基因分析在以下对象中发现了外显子16中的一种新型杂合FLNC变体（NM_001458.4:c.2495_2498delAGTA，杂合；p.K832TfsX45）：i）患有扩张型心肌病且需要心脏移植的索引患者；ii）一名死于心源性猝死的儿子；iii）一名曾经历心搏骤停但幸存的次子；iv）一名患有孤立性骨骼肌肌病的三子。从索引患者获取的心脏组织中，FLNc蛋白水平显著降低，这意味着p.K832TfsX45 FLNc变体很可能导致了相应mRNA的无义介导衰变。对患病心脏组织的形态学分析显示广泛的纤维化重塑、心肌细胞收缩装置的明显退行性改变以及闰盘的严重结构改变。闰盘处的连接蛋白43信号强度减弱，肌原纤维的FLNc标记减弱甚至缺失。蛋白质组分析表明细胞外基质和闰盘蛋白发生了复杂变化。我们的研究结果表明，这种新型的截短型FLNC突变可能导致单倍体不足，从而引发一系列有害的心脏组织退行性变化，广泛的纤维化重塑和闰盘病理改变是与FLNC相关的心肌病伴危及生命的心律失常的结构基础。
