Mutation analysis of SLC7A9 in cystinuria patients in Sweden
Mutation analysis of SLC7A9 in cystinuria patients in Sweden
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DOI：
10.1089/109065703321560886
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发表时间：
2003-03-01
期刊：
影响因子：
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通讯作者：
Söderkvist, P
中科院分区：
文献类型：
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作者：
Harnevik, L;Fjellstedt, E;Söderkvist, P
胱氨酸尿症是一种常染色体隐性遗传病，其特征是尿中胱氨酸和二碱性氨基酸排泄增加，这会导致患者复发的结石形成。已经描述了三种类型的胱氨酸尿症(类型I、II和III)：类型I是由SLC3A1基因突变引起的，而非类型I(II和III)与SLC7A9突变有关。在我们先前工作中报告的53例患者中，包括在单链构象多态(SSCP)筛查中显示SLC7A9突变和/或缺乏或显示SLC3A1突变杂合性的患者。对16例SLC7A9基因的全部编码区和外显子/内含子边界进行了SSCP和DNA测序分析，除1例临床诊断为纯合性胱氨酸尿症外，其余均为纯合性胱氨酸尿症。在患者组中发现了3个新的SLC7A9突变：2个错义突变(P261L和V330M)，1个碱基对缺失(1009Dela)。我们还检测了先前报道的A182T和9个新的多态。V330M和1009delA突变发生在一个个体的不同等位基因上，我们认为这些突变导致了该患者的胱氨酸尿症。1例SLC3A1基因纯合突变患者携带第三个新突变(P261L)。我们的结论是，SLC3A1仍然是瑞典胱氨酸尿症患者的主要致病基因，只有微小的SLC7A9突变是胱氨酸尿症的遗传基础。相当大比例的患者中没有SLC3A1和SLC7A9突变，这意味着可能存在未被分析的部分基因突变，以及未能被所用方法检测到的大量缺失。然而，我们的结果提出了一个问题，即是否其他未知的基因也可能与胱氨酸尿症有关。
Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas nontype I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.