Xiong Huaqi, Chen Yongxiong, Yi Yajun, Tsuchiya Karen, Moeckel Gilbert, Cheung Joseph, Liang Dan, Tham Kyi, Xu Xiaohu, Chen Xing-Zhen, Pei York, Zhao Zhizhuang Jeo, Wu Guanqing
Departments of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Genomics. 2002 Jul;80(1):96-104. doi: 10.1006/geno.2002.6802.
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 approximately 365-kb 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 approximately 11 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.
常染色体隐性多囊肾病（ARPKD）是婴幼儿常见的遗传性肾囊性疾病。通过基因连锁分析，将导致该疾病的基因，即多囊肾和肝病1（PKHD1）基因，定位到人类6号染色体的6p21.1 - p12区域，并进一步定位于由D6S1714 / D6S243（端粒）和D6S1024（着丝粒）标记侧翼的1厘摩遗传区间。我们最近利用克隆策略从肾脏cDNA中鉴定出该遗传区间的一个新基因。PKHD1（暂定）基因编码一种新的3396个氨基酸的蛋白质，与任何已知蛋白质均无明显同源性。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。PKHD1编码一个11.6 kb的转录本，由61个外显子组成，跨越6号染色体6p12 - p11.2上与标记D6S1714相邻的约365 kb基因组区域。Northern印迹分析表明，该基因有离散条带，在约11 kb处有一个峰值信号，表明PKHD1可能有多个可变转录本。Northern印迹分析显示，PKHD1在成人和婴儿肾脏中高表达，在肝脏中弱表达。这种表达模式与ARPKD中观察到的组织受累情况相似。原位杂交分析进一步揭示，PKHD1在肾脏中的表达主要定位于集合管的上皮细胞，这是ARPKD中参与囊肿形成的特定肾小管节段。PKHD1的这些特征使其成为ARPKD的一个强有力的定位候选基因。
