婴儿肥厚型心肌病一家系GAA基因的突变分析

Analysis of the GAA Gene Mutations in a Chinese Family with Infantile Hypertrophic Cardiomyopathy

【目的】鉴定一个婴儿肥厚型心肌病家系GAA基因的致病性突变。【方法】分析一例患病女婴的临床及家系资料;提取先证者及其父母和姐姐的外周血DNA,PCR扩增GAA基因的全部20个外显子及剪接位点序列,对PCR产物进行直接测序。【结果】家系分析表明该病的遗传方式可能为常染色体隐性遗传;心脏彩超提示患儿有肥厚型心肌病;先证者GAA基因有两个复合杂合性突变:遗传自母亲的外显子13的c.1843G>A(p.G615R)错义突变和遗传自父亲的外显子18的c.2608C>T(p.R870X)无义突变。先证者未患病的姐姐只携带了c.2608C>T杂合性突变。该两种突变均尚未在大陆地区患者中发现。该两个突变已被证实可引起突变等位基因编码的蛋白残存的GAA酶活性严重减少。【结论】GAA基因的c.1843G>A和c.2608C>T复合杂合性突变导致了该患儿出现以肥厚型心肌病为特征的经典婴儿型Pompe病(或糖原贮积症Ⅱ型)。该研究进一步证实了c.1843G>A突变与婴儿型Pompe病相关;同时也表明了对常染色体隐性遗传的婴儿肥厚型心肌病进行GAA基因检测或GAA酶活性检测的必要性。

[ Objective ] To identify pathological mutations of the GAA gene in a Chinese family with two patients affected with infantile hypertrophic cardiomyopathy. [ Methods ] The clinical data and the family history of the proband, a 6-month-old affected female infant, were investigated. DNA was extracted from peripheral blood of the proband, her parents and sister. All 20 exons and the intron-exon splice sites of GAA gene were amplified by polymerase chain reaction （PCR）. Mutations were detected by direct sequencing the PCR products. [ Results ] The echocardiography indicated that the infant had hypertrophic cardiomyopathy. Pedigree analysis suggested that the mode of inheritance might be autosomal recessive. The infant was found to be compound heterozygous for two mutations in the GAA gene： c.1843G 〉 A （p.G615R） missense mutation in the exon 13 from her mother and c.2608C 〉 T （p. R870X） nonsense mutation in the exon 18 from her father. The proband＇s unaffected sister only carried the heterozygous c.2608C 〉 T mutation. The c.1843G〉A mutation was first discovered in the patients with infantile form of Pompe disease in Taiwan, and the c. 2608C〉T mutation was first found in the Argentineans patients and then in the German patients. To the best of our knowledge, this is the first report for the two variants in the GAA gene in the China's Mainland. Both the mutant alleles had been verified to code for the mutant protein with very low GAA activity respectively. [Conclusion] The compound heterozygous c.1843G 〉 A and c.2608C 〉 T mutations caused the infant＇s condition, the classic infantile form of Pompe disease （or glycogen storage disease type II） characterized by hypertrophic cardiomyopathy. This study confirms that c. 1843G〉A mutation is related to the classic infantile form of Pompe disease. It also indicates the necessity of performing the analysis of the GAA gene or GAA activity for patients with the autosomal reccesive infantile hypertrophic cardiomyopathy.