Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD) -: art. no. e63
Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD) -: art. no. e63
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DOI：
10.1136/jmg.2005.032318
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发表时间：
2005-10-01
影响因子：
4
通讯作者：
Zerres, K
中科院分区：
文献类型：
--
作者：
Bergmann, C;Küpper, F;Zerres, K
背景：常染色体隐性多囊肾病 ( ARPKD) 是由染色体 6p12 上的 PKHD1（多囊肾和肝病 1）基因突变引起的，该基因是一个跨越 470 kb 基因组 DNA 的大基因。迄今为止，仅描述了编码最长开放阅读框（ORF）的 66 个外显子中的微突变，约占突变的 80%。 目的：检验总体基因组重排和选择性剪接外显子突变导致剩余疾病等位基因子集的假设。 方法：使用 DHPLC 选择性剪接外显子和定量实时聚合酶链反应检测基因组失衡，筛选了 58 名 ARPKD 患者，其中已知 55 个基因在最长的 ORF 中含有一个 PKHD1 点突变。结果：鉴定出三种不同的杂合 PKHD1 缺失和可变剪接外显子中的几个单核苷酸变化。检测到的部分基因缺失很可能是致病性的，而在可变剪接外显子中鉴定出的改变的潜在生物学功能必须等待包含可变外显子及其预测阅读框的转录本的定义。结论：总 PKHD1 缺失占 ARPKD 病例的可检测比例。主要基因组 PKHD1 重排的筛选将进一步改善 ARPKD 的突变分析。
Background: Autosomal recessive polycystic kidney disease ( ARPKD) is caused by mutations in the PKHD1 ( polycystic kidney and hepatic disease 1) gene on chromosome 6p12, a large gene spanning 470 kb of genomic DNA. So far, only micromutations in the 66 exons encoding the longest open reading frame (ORF) have been described, and account for about 80% of mutations.Objective: To test the hypothesis that gross genomic rearrangements and mutations in alternatively spliced exons contribute to a subset of the remaining disease alleles.Methods: Using DHPLC for alternatively spliced exons and quantitative real time polymerase chain reaction to detect genomic imbalances, 58 ARPKD patients were screened, of whom 55 were known to harbour one PKHD1 point mutation in the longest ORF.Results: Three different heterozygous PKHD1 deletions and several single nucleotide changes in alternatively spliced exons were identified. The detected partial gene deletions are most likely pathogenic, while a potential biological function of the alterations identified in alternatively spliced exons must await the definition of transcripts containing alternative exons and their predicted reading frames.Conclusions: Gross PKHD1 deletions account for a detectable proportion of ARPKD cases. Screening for major genomic PKHD1 rearrangements will further improve mutation analysis in ARPKD.