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Identification and Characterization of Pkhd1, the Mouse Orthologue of the Human ARPKD Gene

Yasuyuki Nagasawa^*, Sonja Matthiesen, Luiz F. Onuchic, Xiaoying Hou, Carsten Bergmann^¶, Ernie Esquivel^||, Jan Senderek^¶, Zhiyong Ren, Raoul Zeltner^||, Laszlo Furu^||, Ellis Avner^#, Markus Moser^,&, Stefan Somlo^||, Lisa Guay-Woodford, Reinhard Büttner, Klaus Zerres^¶ and Gregory G. Germino^*

*Department of Medicine and Genetics, Johns Hopkins University, Baltimore, Maryland; Institut of Pathology, University of Bonn, Bonn, Germany; Department of Medicine, University of Sao Paulo, Sao Paulo, Brazil; Department of Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; ^¶Institute of Human Genetics, Technical University of Aachen, Aachen, Germany; ^||Department of Medicine and Genetics, Yale University, New Haven, Connecticut; ^#Department of Pediatrics, Rainbow Babies Children Hospital, Cleveland, Ohio; ^&Max-Planck-Institute for Biochemistry, Martinsried, Germany.

Correspondence to Dr. Klaus Zerres, Institute of Human Genetics, Technical University of Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. Phone: 0241-8080-178; Fax: 0241-8082-580; E-mail: kzerres{at}ukaachen.de; or Dr. Gregory G. Germino, Johns Hopkins University School of Medicine, Division of Nephrology, Ross 958, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-614-0089; Fax: 410-614-5129; E-mail: ggermino@jhmi.edu

ABSTRACT. PKHD1, the gene mutated in human autosomal recessive polycystic kidney disease has recently been identified. Its translation products are predicted to belong to a superfamily of proteins involved in the regulation of cellular adhesion and repulsion. One notable aspect of the gene is its unusually complex pattern of splicing. This study shows that mouse Pkhd1 and its translation products have very similar properties to its human orthologue. Mouse Pkhd1 extends over approximately 500 kb of genomic DNA, includes a minimum of 68 nonoverlapping exons, and exhibits a complex pattern of splicing. The longest ORF encodes a protein of 4059aa predicted to have an N-terminal signal peptide, multiple IPTs and PbH1 repeats, a single transmembrane span (TM), and a short cytoplasmic C-terminus. Although the protein sequence is generally well conserved (approximately 73% average identity), the C-termini share only 55% identity. The pattern of Pkhd1 expression by in situ hybridization was also examined in developing and adult mouse tissues over a range of ages (E12.5 to 3 mo postnatal). High levels of expression were present in renal and biliary tubular structures at all time points examined. Prominent Pkhd1 signals were also found in a number of other organs and tissues. Tissue-specific differences in transcript expression were revealed through the use of single exon probes. These data show that key features of human PKHD1 are highly conserved in the mouse and suggest that the complicated pattern of splicing is likely to be functionally important.

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