Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the γ2-subunit of AMP-Activated protein kinase
Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the γ2-subunit of AMP-Activated protein kinase
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DOI：
10.1203/pdr.0b013e3181462b86
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发表时间：
2007-10-01
影响因子：
3.6
通讯作者：
Dimauro, Salvatore
中科院分区：
文献类型：
--
作者：
Akman, Hasan O.;Sampayo, James N.;Dimauro, Salvatore
一名10周大的女婴，心脏超声显示室间隔和心房壁严重肥厚，心室壁逐渐增厚，并在5个月大时死于吸入性肺炎。尸检显示由于糖原堆积导致心室肥厚和心房壁大量增厚。骨骼肌活检显示游离糖原增加，磷酸化酶b激酶（PHK）活性降低。有报告称在3名患有先天性肥厚型心肌病、糖原贮积和“假性PHK缺乏”的婴儿中，编码AMP活化蛋白激酶（AMPK）γ2亚基的基因（PRKAG2）存在致病性突变（R531Q），这促使我们对该患者的此基因进行筛查。我们在PRKAG2中发现了一种新的（R384T）杂合突变，影响了N末端AMP结合域中的一个精氨酸残基。与R531Q一样，这种突变降低了AMP和ATP与分离的核苷酸结合域的结合，并阻止完整细胞在代谢应激下激活异源三聚体。在患者父亲（唯一可获取的亲本）的DNA中未发现该突变，很可能是新发突变。我们的研究证实，PRKAG2突变可导致致命的婴儿心肌病，且常伴有明显的PHK缺乏。
A 10-wk-old infant girl with severe hypertrophy of the septal and atria] walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the gamma 2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMP-binding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency.