title: PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression.
abstract: 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.
authors.affiliation: Division of Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Hogan
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Griffin
authors.forename: Sandro
authors.initials: S
authors.lastname: Rossetti
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ward
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D019070:Cell Lineage; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D006801:Humans; D007438:Introns; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism*; D014018:Tissue Distribution; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; C451750:PKHD1 protein, human; C478647:PKHD1L1 protein, human; D011956:Receptors, Cell Surface; D012313:RNA