Mutation Analysis of the Entire PKD1 Gene: Genetic and Diagnostic Implications Sandro Rossetti, Lana Strmecki, Vicki Gamble, Sarah Burton, Vicky Sneddon,

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Mutation Analysis of the Entire PKD1 Gene: Genetic and Diagnostic Implications Sandro Rossetti, Lana Strmecki, Vicki Gamble, Sarah Burton, Vicky Sneddon, Belén Peral, Sushmita Roy, Aysin Bakkaloglu, Radovan Komel, Christopher G. Winearls, Peter C. Harris The American Journal of Human Genetics Volume 68, Issue 1, Pages 46-63 (January 2001) DOI: 10.1086/316939 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Diagram showing the fragments employed for mutation screening of the PKD1 gene and the mutations detected. The PKD1 gene (top) and transcript (bottom), showing the intron/exon structure, duplicated region (blue), single-copy coding exons (solid boxes), and 5′ and 3′ UTRs (open boxes). The positions of fragments to amplify the transcript specifically (Spec; blue), plus the PTT fragments (PTT; red) and cDNA sequencing products (cSeq; green), are shown at the bottom. The locations of the PKD1-specific and anchored genomic fragments (Gen; blue), plus the genomic sequencing products (GenSeq; green), are illustrated at the top. The sites of the mutations detected in the 81 different PKD1 pedigrees (P) are shown in the center. Different mutation types are color coded and grouped: splicing mutations, turquoise; frameshifting deletions or insertions, purple; in-frame deletions or insertions, green; nonsense mutations, red; and missense mutations, dark blue. Newly described mutations are shown in boldface type. The American Journal of Human Genetics 2001 68, 46-63DOI: (10.1086/316939) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 Examples of PTT gels. A, Fragment PTT3, transcripted and translated from cDNA of mouse; human (Normal); somatic-cell hybrids, 77-2/1 and P-MWH2A (HG only; lane 2 and 6, respectively); P-SHH1H; whole chromosome 16 (16 hybrid); and the radiation hybrid, Hy145.19 (PKD1 only). The product is only generated in PKD1-containing samples showing the specificity of this PTT assay. Analysis of PKD1 patient and normal cDNA by PTT assays, PTT1 (B) and PTT4 (C). The pedigree number and detected mutation are shown for each sample. Mutant polypeptides are seen as smaller products on the gel. The American Journal of Human Genetics 2001 68, 46-63DOI: (10.1086/316939) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 Examples of direct sequence analysis of patient DNA. A, The missense substitution E2771K, caused by G→A transition at position 8522 nt. B, Two nonsense mutations S225X and Q227X, caused by C→A and C→T substitutions at positions 885 and 890 nt, respectively. C, Normal and patient DNA with the mutation F1992L, 1993delT, caused by a single codon deletion, 6187del3. Note the double peak at the site of a substitution (A and B) and continued double peaks after the deletion (C). The American Journal of Human Genetics 2001 68, 46-63DOI: (10.1086/316939) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 4 Segregation of PKD1 mutations in pedigrees. A, IVS7+1G→A segregates in pedigree 1 (P1). Restriction digest of PKD1 specifically amplified DNA (GenSeq 7) digested with MnI1. A 234-bp fragment (arrow) is found in the affected individuals because of loss of a restriction site. Samples numbered in the pedigree are in the corresponding gel lane. B, Genomic heteroduplex analysis of the mutation 224del13 in pedigree 103 (P103). Heteroduplexes (arrow) and two homoduplex fragments, normal and deleted, can be seen in the affected individuals. The American Journal of Human Genetics 2001 68, 46-63DOI: (10.1086/316939) Copyright © 2001 The American Society of Human Genetics Terms and Conditions