Fabry病家系的α-半乳糖苷酶A基因突变研究

Study of the GLA gene mutation in Chinese patients with Fabry disease

目的通过检测3个Fabry病家系基因突变类型明确基因诊断,并进行家系成员的基因型检测。方法通过PCR和直接测序的方法,对3个Fabry家系的先证者及部分家系成员外周血DNA进行α-半乳糖苷酶A编码GLA基因7个外显子及其相邻内含子的DNA序列检测。结果(1)先证者1的GLA基因7号外显子内1142位点发生碱基缺失(1142delG),1142位碱基G的缺失导致蛋白质翻译在390位氨基酸提前终止,该突变国内外均未见报道;(2)先证者2的GLA基因6号外显子内902位点存在1个错义突变,碱基G被A取代,导致其编码的第301位氨基酸由精氨酸变为谷氨酰胺(902G>A,R301Q);(3)先证者3的GLA基因3号外显子内484位点存在1个错义突变,碱基T被C取代,导致其编码的第142位氨基酸由半胱氨酸变为精氨酸(484T>C,C142R)。在3个家系的部分成员中进行基因检测,检出GLA突变基因携带者共6例,其中男性半合子1例,女性杂合子5例,突变类型均与相应先证者符合。100条正常X染色体对照中均未发现上述位点异常。结论本研究在3个Fabry病家系中检出3种GLA基因突变,其中1142delG为新发现的突变,并在3个家系的部分家系成员中检出男性半合子1例,女性杂合子5例。

Objective To investigate the mutations in Chinese families with Fabry disease. Methods Genomic DNA was extracted from peripheral blood cells of three probands diagnosed as Fabry disease and some family members. Seventy genomic DNA samples extracted from 70 unrelated normal persons were used as control. By PCR and direct sequencing, all 7 exons and their neighboring intronic sequences of the GLA gene of the probands were analyzed. Results Three mutations were identified in 3 probands： （1） deletion of 1 bp at nucleotide 1142 in exon 7 （1142DelG）, leading to premature termination of protein translation at codon 390. （2） 902 G to A transition in exon 6 （codon 301 ）, resulting in replacement of an arginine residue by glutamine （902G 〉A, R301Q）. （3） 484 T to C transition in exon 3 （codon 142）, resulting in replacement of a cysteine residue by arginine （484T 〉C, C142R）. Mutation of GLA gene in 13 relatives of 3 probands was also screened and 6 cases with the same mutation as the relevant proband were found, including 5 heterozygotes and 1 hemizygote. Conclusion Three mutations including one novel mutation （1142DelG） are found in 3 Chinese families with Fabry disease by PCR-DNA sequencing.