Harnevik Lotta, Fjellstedt Erik, Molbaek Annette, Denneberg Torsten, Söderkvist Peter
Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, SE-581 85 Linköping, Sweden.
Genet Test. 2003 Spring;7(1):13-20. doi: 10.1089/109065703321560886.
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.
胱氨酸尿症是一种常染色体隐性疾病，其特征是尿液中胱氨酸和二碱基氨基酸排泄增加，这会导致受影响个体反复形成结石。已描述了胱氨酸尿症的三种亚型（I型、II型和III型）：I型由SLC3A1基因突变引起，而非I型（II型和III型）与SLC7A9基因突变有关。在我们之前的研究报告的53例患者中，本研究纳入了在单链构象多态性（SSCP）筛查中显示SLC7A9基因突变和/或缺乏SLC3A1基因突变或显示SLC3A1基因杂合性的患者。通过SSCP和DNA测序对16例患者的SLC7A9基因的整个编码区和外显子/内含子边界进行了分析，除1例患者外，其余所有患者临床诊断为纯合性胱氨酸尿症患者。在患者组中鉴定出三个新的SLC7A9基因突变：两个错义突变（P261L和V330M），以及一个单碱基对缺失（1009delA）。我们还在患者中检测到先前报道的A182T和九个新的多态性。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。一名SLC3A1基因纯合突变的患者携带了第三个新突变（P261L）。我们得出结论，SLC3A1仍然是瑞典胱氨酸尿症患者中的主要致病基因，SLC7A9基因突变作为胱氨酸尿症的遗传基础的贡献较小。相当一部分患者中不存在SLC3A1和SLC7A9基因突变，这意味着可能存在未分析部分基因的突变，以及所用方法未能检测到的大片段缺失。然而，我们的结果提出了一个问题，即其他尚未知晓的基因是否也可能与胱氨酸尿症有关。
