Hogan Marie C, Griffin Matthew D, Rossetti Sandro, Torres Vicente E, Ward Christopher J, Harris Peter C
Division of Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Hum Mol Genet. 2003 Mar 15;12(6):685-98.
Autosomal-recessive polycystic kidney disease (ARPKD) is caused by mutation to a large gene, PKHD1, encoding a putative receptor protein, fibrocystin. We have identified, through analysis of human genomic sequence, a PKHD1 homolog, PKHDL1, in chromosome region 8q23. The PKHDL1 transcript of 13081 bp was amplified as 16 fragments and sequenced; the sequence of the murine ortholog, Pkhdl1 (chromosome region 15B3) was also determined. PKHDL1 contains 78 exons, covers a genomic region of approximately 168 kb and encodes a large protein, fibrocystin-L. Screening PKHDL1 in ARPKD patients with no PKHD1 mutations revealed several sequence variants but no clear mutations, making it unlikely that it is ARPKD-associated. Human fibrocystin-L is predicted to be a large receptor protein (4243 aa; 466 kDa) with a signal peptide, single transmembrane domain and short cytoplasmic tail. Fibrocystin-L is homologous to fibrocystin throughout most of the extracellular region with overall identity of 25.0% and similarity of 41.5%. Fibrocystin-L has extracellular domains similar to fibrocystin with 14 copies of the TIG domain and two regions of significant homology to the protein TMEM2. Genomic sequence analysis identified no other full-length fibrocystin homologs in humans, mice or other sequenced organisms. The Fugu fish has a fibrocystin-L ortholog but no fibrocystin, suggesting that the newly identified protein may be the ancestral form. PKHDL1 and Pkhdl1 are widely expressed at a low level in most tissues but only detected in blood-derived cell-lines. Low level expression was detected in many primary immune cell subtypes but up-regulated specifically in T lymphocytes, following activation signals, suggesting a role in cellular immunity.
常染色体隐性多囊肾病（ARPKD）是由一个大基因PKHD1发生突变引起的，该基因编码一种假定的受体蛋白——纤维囊素。通过对人类基因组序列的分析，我们在染色体区域8q23中鉴定出了PKHD1的一个同源物PKHDL1。13081 bp的PKHDL1转录本被扩增为16个片段并进行了测序；同时也确定了小鼠直系同源物Pkhdl1（染色体区域15B3）的序列。PKHDL1包含78个外显子，覆盖约168 kb的基因组区域，编码一种大蛋白——纤维囊素-L。在没有PKHD1突变的ARPKD患者中筛查PKHDL1，发现了几个序列变异，但没有明确的突变，这使得它不太可能与ARPKD相关。预测人类纤维囊素-L是一种大的受体蛋白（4243个氨基酸；466 kDa），具有信号肽、单个跨膜结构域和短的细胞质尾巴。纤维囊素-L在大部分细胞外区域与纤维囊素同源，总体一致性为25.0%，相似性为41.5%。纤维囊素-L具有与纤维囊素相似的细胞外结构域，有14个TIG结构域拷贝以及与蛋白TMEM2有显著同源性的两个区域。基因组序列分析在人类、小鼠或其他已测序生物中未发现其他全长纤维囊素同源物。河豚有纤维囊素-L的直系同源物，但没有纤维囊素，这表明新鉴定的蛋白可能是祖先形式。PKHDL1和Pkhdl1在大多数组织中广泛低水平表达，但仅在血液来源的细胞系中检测到。在许多原代免疫细胞亚型中检测到低水平表达，但在激活信号后，T淋巴细胞中特异性上调，提示其在细胞免疫中起作用。
