Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea Peter Heinz-Erian, Thomas Müller, Birgit Krabichler, Melanie Schranz, Christian.

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Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea Peter Heinz-Erian, Thomas Müller, Birgit Krabichler, Melanie Schranz, Christian Becker, Franz Rüschendorf, Peter Nürnberg, Bernard Rossier, Mihailo Vujic, Ian W. Booth, Christer Holmberg, Cisca Wijmenga, Giedre Grigelioniene, C. M. Frank Kneepkens, Stefan Rosipal, Martin Mistrik, Matthias Kappler, Laurent Michaud, Ludwig-Christoph Dóczy, Victoria Mok Siu, Marie Krantz, Heinz Zoller, Gerd Utermann, Andreas R. Janecke The American Journal of Human Genetics Volume 84, Issue 2, Pages 188-196 (February 2009) DOI: 10.1016/j.ajhg.2009.01.004 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Genetic Mapping, an Analysis of the c.593-1G→A Splice-Site Mutation, and Clinical Findings in CSD (A) Pedigree of CSD family no. 1. Numbers below symbols indicate individuals whose DNA was included in the genome-wide SNP-linkage scan, with the exception of patients 671 and 209, whose DNA samples were subsequently shown to harbor the SPINT2 mutation identified in the proband (arrow), and with the exception of individual 15. (B) A LOD score above 3.0 indicates a single region on chromosome 19 that is significantly linked to the disease in this family. The graph represents a parametric LOD score on the y axis in relation to genetic position on the x axis. Human chromosomes are concatenated from p-ter (left) to q-ter (right) on the x axis, and the genetic distance is given in cM. (C) Left: sequence chromatograms show the mutation c.593-1G→A (black arrows) in homozygous and heterozygous state in genomic DNA samples from individuals 343 and 924, respectively. Individual 924 also shows heterozygosity for c.598G→C (p.V200L, rs17850978, red arrow) on the genomic level. The c.598G→C variant and the c.593-1G→A mutation reside on different alleles, as revealed by haplotype analysis (not shown). Right: cDNA sequencing reveals apparent homozygosity for the c.598G→C variant in individual 924. Only an aberrant transcript containing 72 nucleotides of intron 6 is obtained from the patient with the homozygous c.593-1G→A mutation. (D) Facial characteristics of patients CD1(1), A2HE(1), and 343. Note hypertelorism, long philtrum, sparse hair, and photophobia. The American Journal of Human Genetics 2009 84, 188-196DOI: (10.1016/j.ajhg.2009.01.004) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Conservation of the SPINT2 p.Y163C Mutation (A) Alignment of multiple human Kunitz domains from different proteins. The mutated tyrosine is invariantly conserved within the highly conserved catalytic Kunitz domain. (B) Alignment of known and predicted SPINT2 orthologs shows high evolutionary conservation of this mutated tyrosine residue. The American Journal of Human Genetics 2009 84, 188-196DOI: (10.1016/j.ajhg.2009.01.004) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression and Trypsin-Inhibition Analysis of WT and Mutated SPINT2 Proteins (A) Expression of SPINT2 WT and c.1A→T-, p.Y163C-, and c.593-1G→A-mutated proteins in COS-7 cells. (B) Purification of SPINT2 WT and Cys-163-mutated protein showed no quantitative or qualitative differences. (C) Trypsin activity was significantly less inhibited in COS-7 cells transfected with the Y163C SPINT2 mutant as compared with WT protein. The American Journal of Human Genetics 2009 84, 188-196DOI: (10.1016/j.ajhg.2009.01.004) Copyright © 2009 The American Society of Human Genetics Terms and Conditions