Volume 2, Issue 2, Pages (August 1998)

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Volume 2, Issue 2, Pages 247-251 (August 1998) Somatic Mutation in Individual Liver Cysts Supports a Two-Hit Model of Cystogenesis in Autosomal Dominant Polycystic Kidney Disease Terry J Watnick, Vicente E Torres, Michael A Gandolph, Feng Qian, Luiz F Onuchic, Katherine W Klinger, Gregory Landes, Gregory G Germino Molecular Cell Volume 2, Issue 2, Pages 247-251 (August 1998) DOI: 10.1016/S1097-2765(00)80135-5

Figure 1 Genomic Structure of the PKD1 Gene The PKD1 gene contains 46 exons and is bisected by a polypyrimidine tract of ∼2.5 kb (hatched box). The replicated portion of the gene begins in exon 1 and ends in intron 34 (stippled bar). The locations of polymorphisms used for LOH studies and haplotype analysis are indicated. The positions of PKD1-specific, long-range PCR products, 3′LR (∼10 kb) and 5′MR (∼3 kb), are shown along with the primers used for amplification. Molecular Cell 1998 2, 247-251DOI: (10.1016/S1097-2765(00)80135-5)

Figure 2 Loss of Heterozygosity (LOH) for EJ1 in Cysts from Liver Donor JHU415 (A) EJ1 was amplified from the blood of JHU415 as well as DNA isolated from 12 liver cysts and subjected to heteroduplex analysis. The majority of cysts (C) have the same pattern as the blood. C8 and C12, however, demonstrate LOH since heteroduplex formation is no longer seen. C11 shows a novel heteroduplex pattern. (B) Mixing studies were performed to determine which EJ1 allele remained in cysts with either LOH (C8, C12) or a novel heteroduplex pattern (C11). A cyst sample, C1, with a pattern representative of blood was included as a control. Unlabeled EJ1 alleles A1, A2, and Molecular Cell 1998 2, 247-251DOI: (10.1016/S1097-2765(00)80135-5)

Figure 3 Exon 17 and Exon 25 Polymorphisms (PG1 and PG2, Respectively) Segregate with ADPKD in the Family of JHU452 Exons 17 and 25 were amplified from the diluted 5′MR or 3′LR, respectively, of each family member and subjected to restriction digest with MvaI (exon 17) or MspI (exon 25). MvaI digest of exon 17 creates two new fragments of 100 and 82 bp in each affected family member. MspI digest cleaves the PCR product once, creating fragments of 210 and 172 bp in affected family members. All family members, regardless of sex, are represented by triangles. Closed triangles represent affected individuals. The numbers in brackets are the KG8 alleles. (U) represents the uncut PCR product. Molecular Cell 1998 2, 247-251DOI: (10.1016/S1097-2765(00)80135-5)

Figure 4 C4 Contains a 20 bp Deletion on the Normal Haplotype that Disrupts a Consensus Splice Site in Intron 30 (A) Intron-based primers were used to amplify exon 30 from the 3′LR of JHU452 and nine individual cysts. The radiolabeled PCR products were subjected to heteroduplex analysis. C4 contains a novel heteroduplex pattern. (B) A PCR product spanning exons 25–30 was amplified from the 3′LR of C4. This product was cloned and sequenced, and a 20 bp deletion was identified at the exon 30 splice donor site. The sequence of the mutant allele is demonstrated in the reverse orientation, and the deleted base pairs are noted. To clarify the effect of this mutation, the sequences of normal (N) and mutant (M) alleles are noted below in the forward orientation. The vertical bar identifies the position of the exon/intron boundary for the end of exon 30. The dashes represent the deleted base pairs. The arrow shows the sequence of a primer that was designed to amplify only the mutant allele. (C) The “mutant”-specific primer was used to amplify a PCR product of ∼3 kb spanning exons 25–30 directly from cyst DNA (lane 3). This primer would not support amplification from either the blood (lane 2) or the 3′LR (data not shown) of JHU452. A clone with the deletion (lane 1) is included as a positive control. This demonstrates the specificity of the primer and suggests that the deletion was a somatic event not present in the germline of JHU452. (D) Exon 25 was amplified from the mutant-specific PCR product shown in (C) (lane 3), a clone containing the PG2 polymorphism (lane 1), and the 3′LR of JHU452 (lane 2). The products were digested Molecular Cell 1998 2, 247-251DOI: (10.1016/S1097-2765(00)80135-5)