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*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
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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Mutations at a single locus, PKHD1 (polycystic kidney and hepatic disease 1), are responsible for all typical forms of human ARPKD. Using a conventional positional cloning approach, we recently identified human PKHD1 and determined that it is a novel gene with a minimum of 86 exons that are assembled in a complex pattern of alternative splice variants (5). The longest open reading frame is encoded by a 67-exon transcript and predicted to yield a protein of 4074 amino acids with multiple IPT domains, PbH1 repeats, and a single TM near its carboxyl terminus. Multiple other polypeptides, including a set of secreted products, might also be encoded by this locus if any of its alternative transcripts are translated. The predicted translation products are novel proteins that share domain architecture with a superfamily of proteins involved in the regulation of cell proliferation and cellular adhesion and repulsion. We named the gene products polyductin.
Contemporaneous with our efforts, another group used a different strategy to identify PKHD1 (6). These investigators discovered that the locus responsible for ARPKD in the pck rat mapped to a region syntenic to that of human ARPKD (7,8). Taking advantage of the directed genetic mapping capability of the rat, they refined the position of PKHD1 and identified both the rat and human genes. They named the predicted translation product fibrocystin.
The two studies reported similar findings for many key features of PKHD1 and its predicted translation product. Both groups determined that PKHD1 is a very large gene extending over >450 kb of genomic DNA. The two reports identified essentially the same 4074–amino acid protein as the translation product of the longest ORF of PKHD1. Finally, both groups showed a diffuse signal strongest in adult and fetal kidney but also present in liver and pancreas on Northern using PKHD1 cDNA fragments as probes. There were some important differences between the two groups findings, however. Whereas Ward et al. (6) described the occasional amplification of cDNA products with alternative exon usage, we found that the majority of PKHD1 cDNA fragments generated from adult human kidney were comprised of a variable set of exons. We attributed the diffuse Northern blot signal for PKHD1 to the gene’s complicated pattern of gene splicing. Given the extraordinary abundance of alternatively spliced products, we reasoned that this property was likely functionally important.
In this report, we describe the complete sequence of the mouse homologue of PKHD1 (Pkhd1) and show that it undergoes a similarly complex pattern of splicing. We also present a comprehensive survey of its expression pattern in mouse tissues by in situ hybridization and show differential expression pattern for a subset of exons.
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Material and Methods |
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The genomic sequence of Pkhd1 was obtained from both public (Genbank) and proprietary (Celera, Rockville, MD) databases.
Sequence Analysis and Protein Modeling
The genomic structure and orientation of Pkhd1 was established by aligning the confirmed expressed sequences with the interval genomic sequence using BLAST2. BLAST2 was also used to identify regions of homology between the mouse and human gene sequences. All coding exons, untranslated regions (UTRs), introns, alternatively used exons, and Celera transcripts hCT1642763 and hCT1646988 were subject to such analysis. SMART (Simple Modular Architecture Research Tool) (9,10) and PROSITE were used to identify domain architecture and protein motifs. All analyses were performed using default parameters.
Northern Analysis
Probes were amplified using cloned gene fragments as template, gel purified, 32P-labeled using the multi-prime method, and hybridized to both commercial (Clontech and RNWAY [Seegene, Seoul, South Korea] mouse adult MTN blots) and self-made Northern blots. For the latter, 10 to 20 µg of total RNA that had been extracted from freshly harvested adult tissues using Trizol was loaded in each lane. Some of the blots were prepared using 1 to 2 µg of oligo d(T)-enriched RNA/lane (poly-A kit; Qiagen, Chatsworth, CA). Hybridizations were performed at 68°C using ExpressHyb (Clontech) for 16 h and washed in 2xSSC/0.05% sodium dodecyl sulfate (SDS) at room temperature for 40 min and 0.1xSSC/0.1% SDS at 50°C for 40 min. Images were obtained using a PhosphorImager (Molecular Dynamics, Sunnyvale, CA).
In Situ Hybridization of Mouse Pkhd1
In situ hybridization to paraffin-embedded tissue sections was performed as has been previously described (11). Sense and antisense 33P-UTP labeled cRNA probes spanning exons 5 and 41 were used as probes.
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In the course of assembling the complete cDNA, we identified a large number of distinct transcripts that had unique combinations of Pkhd1 exons. Representative examples are presented in Figure 1C. In most cases, the alternatively spliced products lacked a variable number of exons and were thus likely derived from shorter mRNAs. A subset of clones was found to include exons whose splice-site boundaries differed from those used to create the cDNA that encoded the longest ORF. In one clone, we found a unique exon not present in the 67-exon ORF transcript. It should be emphasized that in all circumstances conventional splice site donor and acceptor sequences were used. Interestingly, several of the most dramatically spliced products were identified as ESTs derived from mouse kidney IMAGE cDNA clones (AI16884 from clone 1481021; AI118496 and AI119022 from 1481154; and AI043040 and AI049325 from clone 1432609). These products are particularly notable because they link the most 5' and 3' exons of Pkhd1 in a single transcript of only 3.1 kb. Given that these clones were isolated from a cDNA library generated in the conventional manner, it suggests that the unusual pattern of alternative splicing that we have observed is a general property of Pkhd1 and not simply an artifact resulting from use of PCR-based methods.
We had observed the same phenomenon in our studies of human PKHD1 (5). In the case of the human gene, however, we had identified both a larger number of unique exons (71 versus 68) and exons with alternative boundaries (15 versus 6). Although this may reflect true species differences, it is more likely the result of a less exhaustive analysis of every primer combination using mouse cDNA.
The observation that the human and mouse genes shared complex patterns of splicing prompted us to examine whether specific features were conserved. We compared the specific patterns of splicing, the relative position and sequence of exons that occasionally used alternative splice sites, and the relative position and sequence of unique exons that were not part of the 67 exon longest ORF transcript. We used both cDNA and genomic sequences for this analysis to detect segments of homology not yet represented in our clone set. We found that neither the patterns of exon assembly nor the DNA sequences of most of the alternative exons were similar between the two species. Moreover, no significant homology could be found between the two species even when the translated sequences of alternative exons were compared. Likewise, most of the exons of Celera human transcripts hCT1642763 and hCT1646988 that were not present in any of the published PKHD1 transcripts also lacked homologues in the mouse sequence (5,12).
There were several exceptions, however. Mouse exon 59, like its human counterpart exon 60, is subject to the same alternative splice-site usage. In addition, human PKHD1 exon 38, which is not part of the longest ORF, and hCT1642763 exon B (5) have very high sequence identity to the corresponding segments of the mouse genomic sequence. Significant but lower homology was also detected for human exon 64, another exon that is not part of the longest ORF.
Finally we searched for regions of homology between the genomic sequence of human and mouse Pkhd1, looking for potential exons that have not yet been isolated as part of either cDNA set. We identified 48 segments that had a minimum length of 
200 bp and a minimum of 80% sequence identity. Reanalyzing the genomic segments with exon prediction programs, we determined that a few members of the set were identified as possible exons. Attempts at linking these segments with adjacent exons by PCR of kidney cDNA have been unsuccessful, however.
Expression Features of Pkhd1
One of the more striking aspects of the studies by Ward et al. (6) and Onuchic et al. (5) was the hybridization pattern of PKHD1 on Northern blots of human tissue. We therefore examined the pattern of Pkhd1 expression in mouse tissues using two different cDNA probes derived from exons 5 and 41 of mouse Pkhd1, respectively. Representative results are presented in Figure 2. Both probes detected a predominant band of approximately 13 kb strongly expressed in kidney and weakly in liver, heart, stomach, intestine, muscle, uterus, and placenta (Figure 2, A and B). Interestingly, the exon 41 probe also recognized a small, approximately 1-kb Pkhd1 transcript in testis that was not detected with the exon 5 probe. Hybridization of a blot of kidney tissues with probes for mouse Pkd1 and Pkhd1 confirmed that the predominant message of the latter was smaller than 14 kb, as previously reported by Ward et al. (6) (Figure 2, A through C).
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Strong Pkhd1 signals were also found in a number of organs and tissues other than kidney and liver (Figure 5). High levels of expression were detected in the muscular wall of large vessels, including the thoracic and abdominal aorta, the primordial testis, and dorsal root ganglia. We also detected weak signals in the embryonic lung mesenchyme in close proximity to the respiratory epithelium, in pancreatic ducts, in the developing trachea and in skeletal muscle (data not shown).
Given the results of our Northern blot analyses and cDNA studies, we reasoned that specific cell types or entire organs might express transcripts with unique patterns of exon assembly. We confirmed this hypothesis by comparing the in situ hybridization results obtained using the exon 41 probe with one that detects only exon 5 (Figure 6). These studies demonstrate that transcripts expressed in the wall of large vessels include exon 41 but lack exon 5. Exon 5 was also not detectable in Pkhd1 transcripts in the developing lung or trachea, though it was abundantly present in kidney and liver.
Mouse Polyductin
The full-length translation product of Pkhd1 is predicted to be 4059 aa in length (Supplementary Information, Figure S2). We selected the first in-frame methionine as the likely initiation codon, though an adjacent one could serve in the same capacity. Neither codon has flanking sequences that exactly match the Kozak consensus. Like its human orthologue, mouse polyductin is predicted by SMART to be an integral membrane protein with a 3851 amino acid extracellular amino terminus, a single transmembrane domain, and a very short carboxyl terminus (Figure 7). It has the same general domain structure as human polyductin, with multiple IPT domains (Ig-like, plexin, transcription factor) and PbH1 repeats (parallel beta-helix) in its extracellular segment. Human and mouse polyductin share 73% identity over their complete length, though there are segments with considerably higher (87%) and lower values (40%).
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Mouse and human polyductin sequence also differ considerably in several segments. For example, despite having an identical number of IPT domains, the homology between the two species for the segment of polyductin that contains the cluster of five domains is relatively low at approximately 66%. Likewise, a short segment between PbH1 repeats #2 and #3 of human and the corresponding portion of mouse (i.e., between repeat #1 and #2) is only 42% identical. The most striking finding, however, is that the sequence of the cytoplasmic termini of the two proteins is only 55% identical.
We also sought to determine whether any of the motifs identified by PROSITE were conserved between the species. In fact, several potentially interesting motifs were found common to human and mouse polyductin. For example, two of the three putative cAMP/cGMP phosphorylation sites (PS0004) identified by PROSITE within the carboxyl terminus of human polyductin are conserved in the mouse orthologue (5). PROSITE also identified a putative EF-hand signature sequence (PS00018) in mouse polyductin (820 to 832 aa) that was initially missed in the human orthologue but can be found if one slightly changes the search parameters (822 to 834 aa; 85% similarity to consensus sequence). Using the modified search conditions, a second EF-hand also is predicted by PROSITE in the human protein (3266 to 3278 aa; 91% similarity). The significance of the findings in either species is unclear because none of the motifs are flanked on both sides by alpha-helical domains and all are positioned in extracellular domains. Another finding of uncertain significance is the putative RGD motif (PS00016) of human polyductin, because the mouse orthologue lacks the same.
We previously predicted that the translation products of human polyductin would fall into two classes (5). Members of the first group, which includes the longest continuous ORF, have a single TM domain and are thus likely to be associated with the plasma membrane (polyductin-M), whereas members of the other group, which lacked the TM domain, are likely to be secreted (polyductin-S). Given that mouse Pkhd1 undergoes a complicated pattern of splicing similar to that of humans, we predict its translation products will include both membrane-associated and secreted proteins.
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A number of small differences also were noted. For example, several of the domains and motifs identified by SMART and PROSITE were found to be present in one species but not in the other. Although the absence of these potentially functional elements may in fact reflect true biologic differences between the species, we think the discordant results more likely reflect the limitations of the analytical methods that were used. The consensus sequence patterns used to identify some of the motifs (such as the cell-attachment domain, RGD, or the cAMP/cGMP phosphorylation sites) are very short and thus prone to having a high false positive rate. In the case of the putative EF-hand, we could identify the structure in an identical position in both species only after we lowered the stringency of the search conditions. It is clear that detailed functional analyses will be required to establish which if any of these predictions are valid.
One somewhat surprising finding was the relatively low sequence homology that was observed between the cytoplasmic carboxyl terminus of polyductin of the two species. If polyductin functions as a receptor, one might have expected more conserved regions where the protein interacts with components of intracellular signaling pathways. The observation that the cGMP/cAMP phosphorylation sites are conserved despite the relatively low homology of the C-termini may indicate that they are in fact functionally important.
One of the most striking features of human PKHD1 is its unusual pattern of splicing. More than twenty different types of transcripts were identified in our initial phase of cDNA isolation, and this is likely a gross underestimate (Onuchic L, et al., 2002; unpublished observations). The discovery that mouse Pkhd1 has the same properties and undergoes cell-type–specific alternative splicing supports our hypothesis that the complicated splicing pattern is likely biologically important. Similar findings and conclusions have been reported for the neurexins (13–17). This family of genes encodes cell-surface proteins that are thought to be important for neuronal cell-cell recognition. Just three genes are thought to give rise, through alternative splicing, to thousands of isoforms. Interestingly, the pattern of alternative exon and splice-site usage is very similar to what we have observed for human and mouse Pkhd1. In fact, both Pkhd1 and the neurexins are thought to encode two classes of proteins: a set with a single TM and a second in which members are likely secreted. Cell-type–specific expression of various isoforms is another feature shared by the two groups of genes. In the case of neurexins, alternative splicing has been shown to result in products with different ligand binding properties (13,14). It will be interesting to see if Pkhd1 translation products have similar properties.
The in situ expression data suggest that Pkhd1 may also be important in other cell types and organ systems. As expected, prominent expression of Pkhd1 was detected in even the earliest stage kidney (mesonephros) and was persistent through postnatal life. Likewise, Pkhd1 was expressed in the developing and adult biliary tract, as would be predicted on the basis of the clinical phenotype of individuals with ARPKD. However, moderately high levels of expression were also detected in a number of organs not generally thought to be dysfunctional in the disease. One implication of these findings is that one must reconsider whether there might be other covert or subclinical disease manifestations in ARPKD patients. It is perhaps interesting to note at least two reports of an association of aneurysms and ARPKD (18,19). It also should be noted that our expression data were generated using only two probes. Given the high degree of alternative exon usage in this gene, one might predict that additional probes that detect other exons might yield different results. A comprehensive survey may be required to understand fully the functions of the various isoforms.
Finally, we have described the genomic organization of mouse Pkhd1. These data will prove invaluable for the identification of important regulatory elements. Some of the noncoding conserved elements may fall into this category. The genomic structure will also be essential for the creation of genetically faithful models of human ARPKD. This is necessary because none of the currently available mouse models of ARPKD map to the region of mouse chromosome 1 that contains Pkhd1 (20). We can also use this information to determine whether the complete null phenotype differs appreciably from that observed in humans or rats. Given the complex pattern of splicing of human and mouse Pkhd1, it is possible that many of the mutant alleles may yield partially functional products. If this is the case, the phenotype of a true null may be more severe and have additional phenotypic manifestations. It also will be interesting to cross Pkhd1 mutant mice with mice with ARPKD due to mutations of other genes to determine whether any are members of common pathways.
Electronic Database Information
Accession numbers and URLs for data in this article are as follows:
OMIM: http://www3.ncbi.nlm.nih.gov/Omim/. Genbank: http://www.ncbi.nlm.nih.gov/Genbank/ for the sequences of all 68 exons and the composite cDNA with the longest ORF (acces-sion number AY130764). Unigene: http://www.ncbi.nlm.nih.gov/UniGene/. BLASTP/N/X/2: http://www.ncbi.nlm.nih.gov/blast/. SMART: http://smart.embl-heidelberg.de/. PROSITE: http://ca.expasy.org/. FGenesh: http://genomic.sanger.ac.uk/gf/gf.shtml. GenScan: http://bioweb.pasteur.fr/seqanal/interfaces/genscan.html.
Accession Numbers: PbH1 repeat, SMART #SM0710; Sema domain, SMART #SM0630; PSI domain, SMART #SM0423; IPT domain, SMART #SM0429.
SIM-Alignment tool for proteins: http://us.expasy.org/tools/sim-prot.html.
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