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目的分析Ⅰ型原发性草酸尿症(PH)家系的遗传方式、临床特征及致病基因丙氨酸乙醛酸氨基转移酶(AGT)突变。方法以2012年11月上海交通大学医学院收治的1例PH患者为研究对象,通过家系调查和血尿草酸浓度离子色谱分析,直接测序法分析AGT基因。同时选取100名健康正常人作为对照。结果该家系共有2例患者确诊为Ⅰ型原发性草酸尿症(PH1),遗传特点符合复杂常染色体隐性遗传。AGT基因测序分析发现先证者与其父亲8号外显子均存在一个新的杂合插入突变(C.946_947insAG),在蛋白水平上该突变引起AGT第275位丝氨酸开始的移码突变,导致羧基末端的119个氨基酸替换缩短为异常的38个氨基酸(P.Ser275Arg fs*38),且先证者与其母亲第2号外显子第467位碱基均存在杂合点突变(C.467G>A),导致(P.Gly116Arg),此突变为已报道过的致病点突变。结论一个新的AGT突变位点被确定与隐性遗传性PH1有关。这是国内首次对遗传性PH1进行基因学研究。
Objective To analyze the genetic pattern, clinical characteristics and the mutation of alanine glyoxylate aminotransferase (AGT) in the type Ⅰ primary oxalic acid (PH) pedigree. Methods One case of PH patients admitted to Shanghai Jiao Tong University School of Medicine in November 2012 was studied. The AGT gene was analyzed by direct sequencing using pedigree investigation and ion chromatography with hematuria and acid concentration test. At the same time, 100 healthy controls were selected as control. Results A total of 2 patients in this pedigree were diagnosed as type Ⅰ primary oxalic acid (PH1) and the genetic characteristics were consistent with complex autosomal recessive inheritance. AGT gene sequencing analysis showed that there was a new heterozygous insertion mutation (C.946_947insAG) in exon 8 of probands and his father. At the protein level, this mutation caused a frameshift mutation in the serine at position 275 of AGT, leading to a carboxy-terminal (P.Ser275Arg fs * 38) with a shortened abnormality of119amino acid substitutions, and there was a heterozygous point mutation (C.467G> A) in the probands with the 467nd base of his mother’s exon2, Resulting in (P.Gly116Arg), this mutation has been reported pathogenicity point mutation. Conclusion A new site of AGT mutation was identified as associated with recessive hereditary PH1. This is the first time in China for hereditary PH1 gene research.