A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease
A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease
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DOI：
10.1006/geno.2002.6802
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发表时间：
2002-07-01
期刊：
影响因子：
4.4
通讯作者：
Wu, GQ
中科院分区：
文献类型：
--
作者：
Xiong, HQ;Chen, YX;Wu, GQ
常染色体隐性遗传性多囊肾病（ARPKD）是一种常见的遗传性肾脏囊性疾病，在婴儿和儿童。通过遗传连锁分析，将导致这种疾病的基因称为多囊肾和肝病1（PKHD 1），定位于人类染色体6p21.1-p12，并进一步定位于D 6S 1714/D 6S 243（端粒）和D 6S 1024（着丝粒）标记两侧的1-cM遗传间隔。我们最近确定了一个新的基因在这个遗传间隔从肾脏cDNA，使用克隆策略。PKHD 1基因编码一种新的3396个氨基酸的蛋白质，与任何已知的蛋白质没有明显的同源性。我们将其基因产物命名为“tigmin”，因为它含有多个TIG结构域，这些结构域通常见于含有免疫球蛋白样折叠的蛋白质中。PKHD 1基因编码一个11.6kb的转录本，由61个外显子组成，分布在染色体6p 12-p11.2上与标记D 6S 1714相邻的365 kb基因组区域。北方印迹分析显示，PKHD 1基因在11 kb左右有一个信号峰，显示该基因可能有多个不同的转录本。在北方印迹分析中，PKHD 1在成人和婴儿肾脏中高度表达，而在肝脏中弱表达。这种表达模式与ARPKD中观察到的组织受累相似。原位杂交分析进一步揭示PKHD 1在肾脏中的表达主要定位于集合管的上皮细胞，集合管是参与ARPKD囊肿形成的特定管状段。PKHD 1的这些特征使其成为ARPKD的强有力的位置候选基因。
Autosomal recessive polycystic kidney disease (ARPKD) is a common hereditary renal cystic disease in infants and children. By genetic linkage analyses, the gene responsible for this disease, termed polycystic kidney and hepatic disease 1 (PKHD1), was mapped on human chromosome 6p21.1-p12, and has been further localized to a 1-cM genetic interval flanked by the D6S1714/D6S243 (telomeric) and D6S1024 (centromeric) markers. We recently identified a novel gene in this genetic interval from kidney cDNA, using cloning strategies. The gene PKHD1 (PKHD1-tentative) encodes a novel 3396-amino-acid protein with no apparent homology with any known proteins. We named its gene product "tigmin" because it contains multiple TIG domains, which usually are seen in proteins containing immunoglobulin-like folds. PKHD1 encodes an 11.6-kb transcript and is composed of 61 exons spanning an similar to365kb genomic region on chromosome 6p12-p11.2 adjacent to the marker D6S1714. Northern blot analyses demonstrated that the gene has discrete bands with one peak signal at similar to11 kb, indicating that PKHD1 is likely to have multiple alternative transcripts. PKHD1 is highly expressed in adult and infant kidneys and weakly expressed in liver in northern blot analysis. This expression pattern parallels the tissue involvement observed in ARPKD. In situ hybridization analysis further revealed that the expression of PKHD1 in the kidney is mainly localized to the epithelial cells of the collecting duct, the specific tubular segment involved in cyst formation in ARPKD. These features of PKHD1 make it a strong positional candidate gene for ARPKD.