Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.
Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.
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DOI：
10.1371/journal.pgen.1002427
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发表时间：
2011-12
期刊：
影响因子：
4.5
通讯作者：
Wevers RA
中科院分区：
文献类型：
--
作者：
Lefeber DJ;de Brouwer AP;Morava E;Riemersma M;Schuurs-Hoeijmakers JH;Absmanner B;Verrijp K;van den Akker WM;Huijben K;Steenbergen G;van Reeuwijk J;Jozwiak A;Zucker N;Lorber A;Lammens M;Knopf C;van Bokhoven H;Grünewald S;Lehle L;Kapusta L;Mandel H;Wevers RA
常染色体隐性形式扩张型心肌病（DCM）的遗传原因很少被确定，尽管它们被认为是心脏性猝死和心力衰竭的重要原因，特别是在幼儿中。在这里，我们描述了11例年轻患者（5-13岁）与扩张型心肌病（DCM）的主要表现。代谢研究显示蛋白质N-糖基化缺陷，导致诊断为先天性糖基化障碍（CDG）。在近亲家庭的纯合性定位显示了一个位点与两个已知的基因在N-糖基化途径。在所有个体中，在DOLK中鉴定出致病性突变，DOLK编码负责形成多萜醇-磷酸的多萜醇激酶。患者成纤维细胞的酶分析证实了所有家族中的多萜醇激酶缺乏症。与CDG的一般多系统表现相比，几个个体的非综合征型DCM是显著的。对活检心脏组织中的其他多萜醇-磷酸依赖性糖基化途径的研究表明，α-肌营养不良蛋白聚糖的O-甘露糖基化减少，伴随着其层粘连蛋白结合能力的功能丧失，这与DCM有关。因此，我们确定了一个联合缺乏蛋白N-糖基化和α-肌营养不良聚糖O-甘露糖基化的非综合征型DCM患者由于常染色体隐性DOLK突变。据估计，20%-48%的特发性扩张型心肌病（DCM）患者的病因是遗传。几乎所有目前已知的遗传缺陷都表现为显性遗传，尽管特别是在年幼的儿童中，隐性原因被认为是DCM的重要原因。遗传原因和病理生理机制的知识是至关重要的预后和治疗。在这里，我们研究了几个个体的年轻患者（5-13岁）与特发性和有时无症状的扩张型心肌病。鉴定该基因的关键是发现蛋白质N-糖基化异常。通过纯合性作图和N-糖基化途径的功能知识，可以确定致病基因为多醇激酶（DOLK）。由于DCM在N-糖基化障碍（先天性糖基化障碍，CDG）中非常罕见，并且大多数CDG患者存在多系统受累，因此我们研究了这种危及生命的疾病的潜在病理生理原因。受影响的心脏组织中的生化实验显示α-肌营养不良蛋白聚糖的O-甘露糖基化缺陷，这可能与扩张型心肌病相关。因此，我们的研究结果强调了非综合征型DCM作为DOLK-CDG的一种新表现，通过α-肌营养不良蛋白聚糖的O-甘露糖基化缺陷。
Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations. Idiopathic dilated cardiomyopathy (DCM) is estimated to be of genetic origin in 20%–48% of the patients. Almost all currently known genetic defects show dominant inheritance, although especially in younger children recessive causes have been proposed to contribute considerably to DCM. Knowledge of the genetic causes and pathophysiological mechanisms is essential for prognosis and treatment. Here, we studied several individual young patients (5–13 years old) with idiopathic and sometimes asymptomatic dilated cardiomyopathy. The key to identification of the gene was the finding of abnormal protein N-glycosylation. Via homozygosity mapping and functional knowledge of the N-glycosylation pathway, the causative gene could be identified as dolichol kinase (DOLK). Since DCM is very rare in N-glycosylation disorders (Congenital Disorders of Glycosylation, CDG) and most patients with CDG present with a multisystem involvement, we studied the underlying pathophysiological cause of this life-threatening disease. Biochemical experiments in affected heart tissue showed deficient O-mannosylation of alpha-dystroglycan, which could be correlated with the dilated cardiomyopathy. Our results thus highlight nonsyndromic DCM as a novel presentation of DOLK-CDG, via deficient O-mannosylation of alpha-dystroglycan.
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