Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Hum Mol Genet. 2019 Jun 1;28(11):1919-1929. doi: 10.1093/hmg/ddz032.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
肥厚型心肌病（HCM）是最常见的遗传性心血管疾病，但高达 50%病例的遗传原因仍不清楚。在这里，我们显示 KLHL24 突变导致人类 HCM。通过全基因组连锁分析和外显子组测序，我们在两个有 HCM 的近亲家庭中发现了 KLHL24 的纯合突变。在所鉴定的 11 名年轻受影响的成年人中，有 3 人猝死，1 人因心力衰竭进行了心脏移植。KLHL24 是 Kelch 样蛋白家族的成员，作为底物特异性衔接子与 Cullin E3 泛素连接酶结合。两个家庭受影响个体的心肌和骨骼肌活检显示出特征性改变，包括结蛋白中间丝的积累。斑马鱼同源物 klhl24a 的敲低导致类似于其他 HCM 相关基因描述的心脏缺陷，为 KLHL24 作为 HCM 相关基因提供了额外的支持。我们的发现揭示了 KLHL24 在心脏发育和功能中的关键作用。
