Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells Charles M. Krafchak, Hemant.

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Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells Charles M. Krafchak, Hemant Pawar, Sayoko E. Moroi, Alan Sugar, Paul R. Lichter, David A. Mackey, Shahzad Mian, Theresa Nairus, Victor Elner, Miriam T. Schteingart, Catherine A. Downs, Theresa Guckian Kijek, Jenae M. Johnson, Edward H. Trager, Frank W. Rozsa, Md Nawajes Ali Mandal, Michael P. Epstein, Douglas Vollrath, Radha Ayyagari, Michael Boehnke, Julia E. Richards The American Journal of Human Genetics Volume 77, Issue 5, Pages 694-708 (November 2005) DOI: 10.1086/497348 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Haplotype and mutational analysis of the TCF8 2916_2917delTG mutation in family UM:139. a, Based on sequencing of cloned versions of the two alleles present in UM:139, the frameshift mutation (M) sequence trace is shown on the left, and the corresponding reference (R) sequence, NM_030751, is shown on the right. b, Haplotyping over the 8.55-cM PPCD3 region, with the 2916_2917delTG mutation designated M and the reference allele designated R. All relationships of genotyped individuals are correct as depicted, as determined from the previously reported UM:139 genome scans (Moroi et al. 2003; Shimizu et al. 2004). A large number of nonparticipating descendants of members of generation II do not appear in this figure. Open symbols indicate absence of PPCD, filled symbols indicate affected individuals, flags indicate individuals with hernia, and crossed symbols indicate individuals considered to have indeterminate phenotypes, since they do not have PPCD but do have other corneal findings, such as guttae or FECD. c, Traits that did not cosegregate with the mutation include late-onset hearing loss, migraine headaches, lupus, and arthritis. The locus map shows the order of markers and intermarker distances. The germline of II-8 contains three distinct versions of chromosome 10 shown among his progeny: unaffected haplotype without deletion (III-3 and III-17), affected haplotype plus deletion (III-1, III-5, III-7, III-10, III-11, and III-12), and affected haplotype without deletion (III-15 and IV-28). The three possible explanations include back mutation, a double recombination event, and germline mosaicism in individual II-9. The American Journal of Human Genetics 2005 77, 694-708DOI: (10.1086/497348) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Structure of the TCF8 transcript. Locations of the mutations and the sequence variant relative to exons encoding functional domains are shown. TCF8 encodes a homeodomain (HD) flanked by two zinc-finger clusters (Z1–Z4 and Z5–Z7). An acidic activation domain (AAD) is encoded after the last zinc-finger domain. The American Journal of Human Genetics 2005 77, 694-708DOI: (10.1086/497348) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Additional PPCD families with TCF8 mutations. The genotype of each individual at the relevant locus is displayed. M indicates the mutant allele and R indicates the reference allele. In each case, the mutant sequence trace is on the left and the sequence trace corresponding to the reference allele is on the right. a and b, Families with nonsense mutations. c and d, Families with frameshift mutations. Symbols are as described in figure 1. Relatives in UM:A01 are shown as having indeterminate ocular phenotype because we have not examined them and have no records on them, but since the proband's father has been confirmed and has neither PPCD nor the TCF8 mutation, we do not expect to find PPCD or the TCF8 mutation in that branch of the family. Relationships are confirmed as depicted for all genotyped individuals. The American Journal of Human Genetics 2005 77, 694-708DOI: (10.1086/497348) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Quantitation of transcript levels. Real-time sqPCR on cDNA from various mouse tissues used primers for mouse genes Tcf8 (NM_011546), Vsx1 (NM_054068), and Col8a2 (NM_199473). Eye posterior includes retinal pigment epithelium, choroid, and sclera. The American Journal of Human Genetics 2005 77, 694-708DOI: (10.1086/497348) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Immunohistochemical detection of type IV collagens in corneal endothelium. The corneal endothelium, as marked by vertical arrows, is on the right in each panel. Positive intercytoplasmic staining for COL4A3 in the UM:139 proband's corneal endothelial cells is indicated by horizontal arrows in the sample from the proband COL4A3 panel. In the proband panels, there is a retrocorneal fibrous membrane interposed between the endothelium on the right and the well-defined Descemet membrane on the left. This retrocorneal fibrous membrane is not present in the control panels. COL4A1 and COL4A5 signals are not seen in samples from either the proband or the control. The American Journal of Human Genetics 2005 77, 694-708DOI: (10.1086/497348) Copyright © 2005 The American Society of Human Genetics Terms and Conditions