Cystinuria in children:: Distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes
Cystinuria in children:: Distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes
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DOI：
10.1111/j.1523-1755.2002.kid552.x
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发表时间：
2002-10-01
影响因子：
19.6
通讯作者：
Eggermann, T
中科院分区：
文献类型：
--
作者：
Botzenhart, E;Vester, U;Eggermann, T
背景胱氨酸尿症是一种常见的遗传性疾病，肾脏对胱氨酸、鸟氨酸、赖氨酸和精氨酸的重吸收缺陷导致肾结石。迄今为止，已确定了两个相关基因：编码肾胱氨酸转运系统rbAT/B（0，+）AT重链rbAT的SLC 3A 1基因突变导致I型胱氨酸尿症，而其轻链B（0，+）AT基因SLC 7A 9的变异体已在非I型胱氨酸尿症中得到证实。在这项研究中，我们在一组患有胱氨酸尿症的儿童中寻找这两种基因的突变。对来自16个家族的21例胱氨酸尿症患儿进行了SLC 3A 1和SLC 7A 9基因突变分析。根据父母的尿氨基酸排泄谱对患者进行分类。此外，对10名未分类的患者进行了基因组变异筛查。筛选技术包括单链构象多态性分析、限制性内切酶分析和直接测序。在SLC 3A 1中发现了两个新的突变，在SLC 7A 9中发现了三个;三个是错义突变，两个是移码突变。在儿科患者中，在54%的I型（SLC 3A 1）和25%的非I型（SLC 7A 9）染色体中发现了突变。对于这组患者，两种基因突变的总检出率为46.6%。在未分类的10名患者的队列中，确定了70%的突变。M467 T和G105 R分别是SLC 3A 1和SLC 7A 9的优势突变，T216 M是土耳其和希腊的主要突变。儿童SLC 3A 1和SLC 7A 9突变的检出率为54%，SLC 3A 1基因为I型染色体，SLC 7A 9基因为非I型染色体，突变率为25%。它低于10例未分类的胱氨酸尿症患者，尽管第一组的临床特征更为严格;此外，观察到不同的突变谱。在许多患者中缺乏可检测的突变表明其他尚未确定的基因参与胱氨酸尿症的可能性。我们不能将疾病的严重程度与小儿患者的胱氨酸尿类型联系起来。
Background. Cystinuria is a common inherited disorder of defective renal reabsorption of cystine, ornithine, lysine and arginine leading to nephrolithiasis. Two responsible genes have been identified so far: Mutations in the SLC3A1 gene encoding the heavy chain rbAT of the renal cystine transport system rbAT/b(0,+) AT cause cystinuria type I, while variants in SLC7A9 , the gene of its light chain b(0,+) AT, have been demonstrated in non-type I cystinuria. In this study, we searched for mutations in both genes in a cohort of children with cystinuria.Methods. Twenty-one cystinuric children from 16 families were analyzed by mutational analysis of the genes SLC3A1 and the SLC7A9 . The patients were classified by the urinary amino acid excretion profile of their parents. Additionally, 10 unclassified patients were screened for genomic variants. The screening techniques included single strand conformation polymorphism analysis, restriction assays and direct sequencing.Results. Two novel mutations were identified in SLC3A1 and three in SLC7A9 ; three were missense mutations and two frameshift mutations. In the pediatric patients, mutations were found in 54% of type I (SLC3A1 ) and in 25% of non-type I (SLC7A9 ) chromosomes. For this group of patients a total detection rate of 46.6% for mutations in both genes was delineated. In the cohort of unclassified 10 patients, 70% of mutations were determined. M467T and G105R were the preponderant mutations in SLC3A1 and SLC7A9 , respectively; T216M was the major mutation in Turkey and Greece.Conclusions. The detection rate for mutations in SLC3A1 and SLC7A9 in children was 54% in the SLC3A1 gene for type I chromosomes and 25% in the SLC7A9 gene for non-type I chromosomes. It was lower than that in 10 further patients with an unclassified cystinuria, although the clinical characterization in the first group was more stringent; additionally, different spectrums of mutations were observed. The lack of detectable mutations in many patients indicates the possibility of other yet unidentified genes involved in cystinuria. We could not correlate the severity of the disease to the type of cystinuria in the pediatric patients.