Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency
Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency
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DOI：
10.1086/430840
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发表时间：
2005-06-01
影响因子：
9.8
通讯作者：
Kilimann, MW
中科院分区：
文献类型：
--
作者：
Burwinkel, B;Scott, JW;Kilimann, MW
致死性先天性非溶酶体心脏糖原累积症被认为是磷酸化酶激酶缺乏症的一种亚型，但其潜在的基因和突变尚未确定。分析四个散发的，无关的患者，我们发现没有突变，无论是在8个基因编码磷酸化酶激酶亚基或在两个基因编码的肌肉和大脑的糖原磷酸化酶亚型。然而，在5名患者中，我们发现了PRKAG 2基因的相同杂合R531 Q错义突变，该基因编码AMP活化蛋白激酶的γ 2亚基，这是能量平衡的关键调节因子。重组R531 Q突变体蛋白的生化表征显示，对调节核苷酸AMP和ATP的结合亲和力降低> 100倍，但基础活性增强，α亚基的磷酸化增加。其他PRKAG 2错义突变先前在伴有沃尔夫-帕金森-白色综合征的常染色体显性肥厚型心肌病患者中发现，其特征为青少年至成人临床发作、中度心脏糖原累积症、兴奋传导紊乱、中年心脏性猝死风险以及与R531 Q突变相似但不太严重的分子扰动。因此，PRKAG 2中反复出现的杂合R531 Q错义突变引起胎儿症状性发作和快速致死过程的大量非溶酶体心脏糖原累积症，构成了具有沃尔夫-帕金森-白色综合征的肥厚型心肌病的基因型和临床独特变体。R531 Q和其他PRKAG 2突变增强了AMP活化蛋白激酶的基础活性和α亚基磷酸化，解释了PRKAG 2疾病突变的显性性质。由于并非所有病例均显示PRKAG 2突变，因此致死性先天性非溶酶体心脏糖原累积症似乎具有遗传异质性。然而，心脏特异性原发性磷酸化酶激酶缺乏症的存在是值得怀疑的，因为没有发现磷酸化酶激酶突变。
Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified. Analyzing four sporadic, unrelated patients, we found no mutations either in the eight genes encoding phosphorylase kinase subunits or in the two genes encoding the muscle and brain isoforms of glycogen phosphorylase. However, in three of five patients, we identified identical heterozygous R531Q missense mutations of the PRKAG2 gene, which encodes the gamma 2-subunit of AMP-activated protein kinase, a key regulator of energy balance. Biochemical characterization of the recombinant R531Q mutant protein showed > 100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha-subunit. Other PRKAG2 missense mutations were previously identified in patients with autosomal dominant hypertrophic cardiomyopathy withWolffParkinson- White syndrome, characterized by juvenile-to-adult clinical onset, moderate cardiac glycogenosis, disturbed excitation conduction, risk of sudden cardiac death in midlife, and molecular perturbations that are similar to-but less severe than-those observed for the R531Q mutation. Thus, recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. R531Q and other PRKAG2 mutations enhance the basal activity and alpha-subunit phosphorylation of AMP-activated protein kinase, explaining the dominant nature of PRKAG2 disease mutations. Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous. However, the existence of a heart-specific primary phosphorylase kinase deficiency is questionable, because no phosphorylase kinase mutations were found.