Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S

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Mutations in PRKCSH Cause Isolated Autosomal Dominant Polycystic Liver Disease Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S. Kamath, Bernard F. King, Vicente E. Torres, Stefan Somlo The American Journal of Human Genetics Volume 72, Issue 3, Pages 691-703 (March 2003) DOI: 10.1086/368295 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Refinement of the genetic interval for ADPLD. A, Partial representation of the previously published family 1 (Reynolds et al. 2000), showing the disease-associated haplotype (black bar) and critical recombination events in newly recruited individuals (red boxes). Family 7 is a newly ascertained kindred with possible linkage and a centromeric recombination. B, Schematic representation of the disease-associated haplotypes (all red) in two large kindreds (Reynolds et al. 2000) and family 7, along with critical recombinant chromosomes that define the closest flanking markers (red boxes). Individual identifications correspond to previously published pedigrees for families 1 and 2 (Reynolds et al. 2000). The American Journal of Human Genetics 2003 72, 691-703DOI: (10.1086/368295) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Positional cloning strategy for ADPLD. A, Genetic map position for microsatellite markers used in linkage mapping. Sex-averaged genetic distances (in cM), from the Marshfield map, are shown. B, Physical map of critical interval, showing newly identified markers including the closest flanking microsatellites CA267 and CA048 (bold). C, Partial representation of known genes and their direction of transcription (arrows). ZNF gene region, ∼1 Mb containing zinc finger genes, that is not conserved in the mouse genome. D, Genomic organization of PRKCSH; exons indicated by vertical bars. The American Journal of Human Genetics 2003 72, 691-703DOI: (10.1086/368295) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutations in PRKCSH in ADPLD. A, Sequence electropherograms showing mutant (affected) and wild-type (control) sequences. All template DNA was genomic except as indicated for the IVS16+1delGT mutation where both genomic (left) and RT-PCR (right) was analyzed. Six mutations are shown. B, Segregation of mutations in families 1 (IVS16+1delGT), 2 (C1237T), and 7 (C1266G), as analyzed by DHPLC. Only selected traces are shown, but the entire family was analyzed. Individual identifications correspond to previously published pedigrees (Reynolds et al. 2000) and figure 1. The American Journal of Human Genetics 2003 72, 691-703DOI: (10.1086/368295) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression and conservation of PRKCSH. A, Tissue northern showing expression of PRKCSH in all tissues including liver and kidney. The transcript size is ∼2.5-3.0 kb with skeletal muscle showing evidence of a transcript >7.0 kb and cardiac muscle perhaps having a pair of transcripts in the 2.5-3.0 kb range. B, High degree of sequence conservation from C. elegans to humans. S. pombe and A. thaliana also have highly conserved PRKCSH homologs (not shown). The American Journal of Human Genetics 2003 72, 691-703DOI: (10.1086/368295) Copyright © 2003 The American Society of Human Genetics Terms and Conditions