Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1)
Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1)
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DOI：
10.1097/01.asn.0000039578.55705.6e
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发表时间：
2003-01-01
影响因子：
13.6
通讯作者：
Zerres, K
中科院分区：
文献类型：
--
作者：
Bergmann, C;Senderek, J;Zerres, K
常染色体隐性遗传性多囊肾病（ARPKD/PKHD 1）是儿童期肾脏相关和肝脏相关发病率和死亡率的重要原因。最近，染色体6p21.1-p12上PKHD 1基因的突变已被确定为ARPKD的分子病因。最长的连续开放阅读框（ORF）由67-外显子转录物编码，并预测产生迄今未知功能的4074-氨基酸蛋白质（“多导管蛋白”）。到目前为止，共描述了29种不同的PKHD 1突变。本研究报告了90例ARPKD患者的突变筛查，并确定了110个等位基因的突变，检出率为61%。其中34个突变以前没有报道过。在40例患者中发现了两个潜在的突变，在30例病例中发现了一个突变，在其余染色体上没有检测到突变。发现突变分散在整个基因中，没有证据表明在特定位点聚集。约45%的变化被预测为截短蛋白质。所有的错义突变都是非保守的，受影响的氨基酸残基在鼠多导管蛋白直向同源物中被发现是保守的。一个复发性错义突变（T36 M）可能代表突变热点，并发生在各种人群中。两个创始突变（R496 X和V3471 G）占芬兰人群PKHD 1突变的60%。可以针对突变类型而不是个体突变位点建立初步的基因型-表型相关性。所有携带两个截短突变的患者表现出严重的表型与围产期或新生儿死亡。PKHD 1突变分析是一个强有力的工具，以建立在一个给定的家庭ARPKD的分子原因。突变的直接鉴定允许明确的诊断和准确的遗传咨询，即使在家庭显示诊断挑战。cbergmann@ukaachen.de.
Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074-amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges. cbergmann@ukaachen.de.