Zhou Chi, Huang Jin, Cui Guanglin, Zeng Hesong, Wang Dao Wen, Zhou Qiang
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
Division of Hematology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
BMC Med Genet. 2018 Dec 27;19(1):219. doi: 10.1186/s12881-018-0734-2.
Fabry disease is an X-linked recessive lysosomal disorder caused by deficient enzymatic activity of α-galactosidase A (α-Gal A). The insufficient enzymatic activity leads to excessive accumulation of glycosphingolipids, the substrates of the enzyme, in lysosomes in organs and tissues. Mutations in the α-Gal A gene (GLA, Xq22) have been proven to be responsible for Fabry disease.
In this study, we report a four-generation pedigree with left ventricular hypertrophy and chronic renal failure that was diagnosed by sequencing the GLA gene. An over expression system was constructed to evaluate the function of the detected mutation.
We identified a novel mutation in exon 6 of the GLA gene, p.Asn278Lys, which completely co-segregated with the disease phenotype. The protein level of α-Gal A was significantly lower in the variant group than in the wild-type group; additionally, the pharmacological chaperone 1-deoxy-galactonojirimycin (DGJ) effectively normalized the enzyme activity of α-Gal A and its decline at the protein level.
This study is the first to report a novel loss-of-function mutation, p.Asn278Lys, in exon 6 of the GLA gene as a genetic aetiology for Fabry disease. In addition, we analysed the feasibility of DGJ as a therapeutic approach for this particular GLA mutation.
法布里病是一种X连锁隐性溶酶体疾病，由α-半乳糖苷酶A（α-Gal A）的酶活性缺乏引起。酶活性不足导致该酶的底物糖鞘脂在器官和组织的溶酶体中过度积累。α-Gal A基因（GLA，位于Xq22）的突变已被证实是法布里病的病因。
在本研究中，我们报告了一个通过对GLA基因进行测序诊断为左心室肥厚和慢性肾衰竭的四代家系。构建了一个过表达系统来评估检测到的突变的功能。
我们在GLA基因的第6外显子中鉴定出一个新的突变，p.Asn278Lys，它与疾病表型完全共分离。α-Gal A的蛋白水平在变异组中显著低于野生型组；此外，药物伴侣1-脱氧半乳糖野黑霉素（DGJ）有效地使α-Gal A的酶活性及其在蛋白水平的下降正常化。
本研究首次报告了GLA基因第6外显子中的一个新的功能丧失突变p.Asn278Lys作为法布里病的遗传病因。此外，我们分析了DGJ作为针对这种特定GLA突变的治疗方法的可行性。
