Meconium Ileus Caused by Mutations in GUCY2C, Encoding the CFTR-Activating Guanylate Cyclase 2C Hila Romi, Idan Cohen, Daniella Landau, Suliman Alkrinawi,

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Meconium Ileus Caused by Mutations in GUCY2C, Encoding the CFTR-Activating Guanylate Cyclase 2C Hila Romi, Idan Cohen, Daniella Landau, Suliman Alkrinawi, Baruch Yerushalmi, Reli Hershkovitz, Nitza Newman-Heiman, Garry R. Cutting, Rivka Ofir, Sara Sivan, Ohad S. Birk The American Journal of Human Genetics Volume 90, Issue 5, Pages 893-899 (May 2012) DOI: 10.1016/j.ajhg.2012.03.022 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Trees and Linkage Analysis Results (A) The Israeli-Bedouin Kindred affected with non-CF MI; family 1 and family 2 are not related. (B) Linkage analysis results (chromosome 12p13, partial pedigree of family 1): the haplotype showing the homozygosity region is boxed. Physical locations of the markers are shown. Individuals VII:8, VII:9 defined the upper boundary of the locus and individual VII:23 defined the lower boundary. For tested individuals, the c.1160A>G mutation status of each allele is marked as wild-type (WT) or mutant (M). The American Journal of Human Genetics 2012 90, 893-899DOI: (10.1016/j.ajhg.2012.03.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 The c.1160A>G and c.2270dupA GUCY2C Mutations: Homozygosity for the Wild-Type Allele (A–F) Heterozygosity for the wild-type (A and D) and the mutated alleles (B and E) and homozygosity for the mutated allele (C and F) in normal obligatory carriers and affected individuals of families 1 (A, B, and C) and 2 (D, E, and F). (G) The p.Asp387Gly amino acid substitution: multiple alignment and conservation analysis (ClustalW) of human GUCY2C with its orthologs. (the asterisk [∗] represents the mutated amino acid). (H) The p.Asn757Lysfs∗2 mutation: deleting the functional domain of the enzyme (SMART). The American Journal of Human Genetics 2012 90, 893-899DOI: (10.1016/j.ajhg.2012.03.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Functional Analysis of the c.1160A>G Mutation that Produces p.Asp387Gly (A and B) Immunoblot analysis showing equal amounts of wild-type (GCC) and mutant (GCCD387G) protein in stable transfected HEK293 cell lines used for testing GUCY2C activity. (C) GUCY2C activity in the presence (+Sta) or absence (no Sta) of E. coli heat-stable enterotoxin STa, tested in HEK293 cells stably transfected with either empty pcDNA vector (negative control) or wild-type (GCC) or mutant (GCCD387G) GUCY2C. Each experiment represents mean ± standard deviation of three repeats. Similar results obtained for three different pairs of cell lines stably overexpressing equal amounts of mutant and wild-type GUCY2C. The American Journal of Human Genetics 2012 90, 893-899DOI: (10.1016/j.ajhg.2012.03.022) Copyright © 2012 The American Society of Human Genetics Terms and Conditions