PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor.

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PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats Luiz F. Onuchic, Laszlo Furu, Yasuyuki Nagasawa, Xiaoying Hou, Thomas Eggermann, Zhiyong Ren, Carsten Bergmann, Jan Senderek, Ernie Esquivel, Raoul Zeltner, Sabine Rudnik-Schöneborn, Michael Mrug, William Sweeney, Ellis D. Avner, Klaus Zerres, Lisa M. Guay-Woodford, Stefan Somlo, Gregory G. Germino The American Journal of Human Genetics Volume 70, Issue 5, Pages 1305-1317 (May 2002) DOI: 10.1086/340448 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Chromosomal localization and genomic organization of PKHD1. A, Schematic representation of chromosome 6p12. Currently known genes are identified on the far left (italics), and STSs/polymorphic markers are on the right. The closest flanking genetic markers that define the minimal PKHD1 interval are indicated (boldface). Not all of the 35 overlapping sets of expressed sequences described in the text are shown. B, Genomic organization of PKHD1. Exons identified by numbers have been shown to be part of PKHD1 transcripts. Letters indicate exons that belong to either hCT1642763 or hCT1646988 and that have not been confirmed by our analyses. The black diamond (♦) identifies, in hCT1642763 and hCT1646988, overlapping exons whose boundaries differ from those used in the present study. Arrows indicate the positions of the Gene Unit 6 and Gene Unit 442L12 transcripts described in the text. C, BACs and PACs sequenced by the Sanger Centre that cover the interval. The American Journal of Human Genetics 2002 70, 1305-1317DOI: (10.1086/340448) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 PKHD1 expression profile. A, Human adult multiple-tissue northern blot probed with PKHD1 exon 59: lane 1, pancreas; lane 2, kidney; lane 3, skeletal muscle; lane 4, liver; lane 5, lung; lane 6, placenta; lane 7, brain; lane 8, heart. B, Same blot as in panel A, probed with PKD1. The arrow indicates the position of a known splicing variant of PKD1. C, Human fetal multiple-tissue northern blot probed with PKHD1: lane, 1, kidney; lane 2, liver; lane 3, lung; lane 4, brain. D, Same blot as in panel C, probed with PKD1. The American Journal of Human Genetics 2002 70, 1305-1317DOI: (10.1086/340448) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Structure of full-length PKHD1 and its splicing variants. A, Set of 71 nonoverlapping exons that spans the entire length of PKHD1 (upper row) and 15 additional overlapping exons that use different splice sites (gray boxes, lower row). Exons, which are not present in the cDNA that encodes the longest ORF, are indicated by hatched boxes. The position of important protein domains is indicated. B, Approximate location of each primer set used to amplify various cDNAs, with representative set of amplified products (below each schema). White boxes indicate noncoding exons in the corresponding transcripts while gray boxes identify exons with alternative boundaries (A). The templates used for each amplification are as follows: human adult kidney double-stranded cDNA for primer sets 1–4, 6, and 8; human kidney mRNA and total RNA for primer sets 5 and 7; human adult kidney cDNA library for primer set 9. “SC” indicates approximate location of stop codons, and “ORF” indicates that an open reading frame extends throughout the length of the fragment. C, Longest ORF identified by RT-PCR/cDNA amplification. This ORF is the composite sequence of products 2.1 and 4.1 of panel B and includes a total of 67 exons. The American Journal of Human Genetics 2002 70, 1305-1317DOI: (10.1086/340448) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 PKHD1 mutations in families studied. A, Representative family-segregation analyses of PKHD1 mutations for patients AL 1, AL 11, AL 36, AL 48, AL 52, and 340/1395 (see table 1). Sequence electropherograms showing wild-type and mutant sequences for amplicons containing the respective variants in each family are indicated on the right of each pedigree figure. Traces labeled “mutant” show heterozygous alterations in genomic PCR products. Segregation of the mutant allele (denoted by “Ex” followed by the exon number) is shown for each kindred studied. AL 1 has two missense changes, whereas AL 11, AL 36, and AL 48 each have a missense and a frameshifting mutation. Patient 340/1395 has two frameshifting mutations. AL 52 and her sibling, products of a consanguineous union, are homozygous for the Ex32 mutation (trace labeled AL 52). The Ex32 trace labeled “mutant” is from the heterozygous father. Black symbols denote affected individuals; white symbols denote unaffected individuals. B, Representative DHPLC profiles for several sequence variants in families with PKHD1 (see panel A and table 1). Black traces indicate control profiles; red traces indicate patient variant profiles (the red trace is displaced upward to facilitate comparison). The American Journal of Human Genetics 2002 70, 1305-1317DOI: (10.1086/340448) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 Structure of polyductin and related proteins. Multiple tandemly repeated IPT domains are common features of the group. Polyductin-M shares the general structure of the HGFR and plexin A3, in having a long extracellular domain, a single TM domain, and a short cytoplasmic carboxyl terminus, whereas polyductin-S is more like D86. The American Journal of Human Genetics 2002 70, 1305-1317DOI: (10.1086/340448) Copyright © 2002 The American Society of Human Genetics Terms and Conditions