Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M

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Asymmetric Lower-Limb Malformations in Individuals with Homeobox PITX1 Gene Mutation Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M. Desruisseau, Jacqueline T. Hecht, Carol A. Wise, Anne M. Bowcock, Matthew B. Dobbs The American Journal of Human Genetics Volume 83, Issue 5, Pages 616-622 (November 2008) DOI: 10.1016/j.ajhg.2008.10.004 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Complex Bilateral Congenital Abnormalities of the Lower Extremities of Proband of Family CF5171 Showing Greater Involvement on the Right Side (A) Photograph of the proband demonstrating bilateral duplicated great toes and bilateral clubfoot. The clubfoot is more severe on the right. (B) Radiographs of the digits and rays of both feet, showing bilateral duplication of the first toe, as well as partial duplication of the first metatarsal on the right foot. (C) Radiographs of the lower limb showing absence of the tibia on the right only. The American Journal of Human Genetics 2008 83, 616-622DOI: (10.1016/j.ajhg.2008.10.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Linkage Analysis of Family 5171 with Multiple Lower-Limb Malformations Genome-wide parametric multipoint linkage was performed with GENEHUNTER16 with Affymetrix 10K array data from family 5171. Autosomal-dominant inheritance with 70% penetrance, a disease allele frequency of 0.01%, and no phenocopies were assumed for the analysis. Human chromosomes are concatenated from the p terminal (left) to the q terminal (right) on the x axis. The LOD score (y axis) is correlated to the physical location of human chromosome on the x axis and displayed with EasyLinkage software.41,42 The American Journal of Human Genetics 2008 83, 616-622DOI: (10.1016/j.ajhg.2008.10.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Haplotype Analysis Indicating Markers on Chromosome 5q23.3-q31.2 Common to All Affected Individuals Haplotypes were created with GENEHUNTER and viewed on Haplopainter.43 Presence or absence of the PITX1 E130K mutation is noted with (+) or (−). The arrow indicates the proband. The American Journal of Human Genetics 2008 83, 616-622DOI: (10.1016/j.ajhg.2008.10.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Identification of a PITX1 Mutation in the Highly Conserved Homeodomain Segregating with Clubfoot in Family 5171 (A) Chromatogram showing PITX1 mutation c.388G→A resulting in missense mutation E130K. (B) Ribbon diagram of the PITX2 homeodomain-DNA helix showing the position of the side chain (yellow) of the glutamic acid at position 42 corresponding to PITX1 E130K. The PITX1 E130K mutation lies within the critically important homeodomain third helix (shown to the left in blue, viewed end on) that interacts directly with the major groove of DNA (multicolored at right). We used the Swiss PDB DeepView program (see Web Resources) to visualize the corresponding structural location of the PITX1 E130K mutation on the PITX2 sequence bound to its consensus DNA site (TAATCC)18 (accession code 1YZ8). Within the homeodomain shown, there is 97% amino acid identity between PITX1 and PITX2. (C) Glutamic acid at homeodomain position 42 (corresponding to PITX1 E130K) is conserved in all human PITX family members, across species including Fugu (Takifugu rubripes), and in other nonbicoid homeodomain genes, including PAX7. Sequences were aligned with CLUSTALW (see Web Resources). The American Journal of Human Genetics 2008 83, 616-622DOI: (10.1016/j.ajhg.2008.10.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Reduced Transactivation Ability and Dominant-Negative Effects of PITX1 E130K Mutation (A) Western blot of equal amounts of COS7 cell extracts from a single transfection experiment probed with PITX1 antibody or actin antibody. COS7 cells were transfected with the TK-Bic reporter DNA alone (lane 1) or cotransfected with WT PITX1 (lane 2), or PITX1 E130K plasmids (lane 3). (B) Immunofluorescence staining of transfected COS7 cells showing absent staining with PITX1 antibody in untransfected cells, and similar nuclear staining in cells transfected with either WT PITX1 or PITX1 E130K plasmid. (C) Results of a luciferase reporter assay from COS7 cells transfected with TK-Bic reporter DNA alone or cotransfected with WT PITX1, PITX1 E130K, or equal amounts of both WT PITX1 and PITX1 E130K mutant. There was reduced transactivation ability of PITX1 E130K mutant compared to WT PITX1 (∗p = 0.034). Cotransfection of equal amount of PITX1 E130K with WT PITX1 also resulted in reduced activity compared to WT PITX1 alone (∗∗p = 0.016). Activity is shown as mean fold activation compared to reporter alone ±SE from three independent experiments performed in triplicate. (D) Dose-dependent decrease in luciferase reporter activation by PITX1 when cotransfected with varying amounts of PITX1 E130K plasmid. COS7 cells were transfected with TK-Bic luciferase reporter, WT PITX1 plasmid, and the indicated amount (ug) of either PITX1 E130K mutant or WT PITX1. Activation was reduced when WT PITX1 plasmid was cotransfected with PITX1 E130K mutant compared to cotransfection with equal amount (5 ug) of WT PITX1 (∗p = 0.03). The data represent the three independent experiments with the mean fold activation ±SE. The American Journal of Human Genetics 2008 83, 616-622DOI: (10.1016/j.ajhg.2008.10.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions