Peter Ianakiev, Michael W

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Split-Hand/Split-Foot Malformation Is Caused by Mutations in the p63 Gene on 3q27 Peter Ianakiev, Michael W. Kilpatrick, Iva Toudjarska, Donald Basel, Peter Beighton, Petros Tsipouras The American Journal of Human Genetics Volume 67, Issue 1, Pages 59-66 (July 2000) DOI: 10.1086/302972 Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 1 A, Family R (left upper and lower panels). Note the “lobster-claw” anomaly of the hands and feet. Family A (right upper and lower panels). Note the median clefts and syndactyly. B, Previously reported (Spranger and Schapera 1988) radiograph of family R (left). Note monodactyly with triphalangeal thumb and duplication of the distal phalanx. Family A (center and right) shows absence of the phalanges of the second and third digits in both foot and hand. The American Journal of Human Genetics 2000 67, 59-66DOI: (10.1086/302972) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 2 Extended pedigrees of family A (top) and family R (bottom). Individuals whose DNA was tested are indicated by an asterisk. The phenotypic status of individuals in generations I and II of family R is unknown. The American Journal of Human Genetics 2000 67, 59-66DOI: (10.1086/302972) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 3 A, Schematic representation of exons 4–8 of the p63 gene, the region that contains the DNA-binding domain. Exons 4–8 were amplified individually from genomic DNA samples, and the resulting fragments were analyzed by means of direct sequence analysis. The K194E and R280C mutations, present in exons 5 and 7, respectively, are shown in comparison with the wild-type sequence. B, Identification of the K194E and R280C mutations in individuals with SHFM. The individual with the K194E mutation is heterozygous A/G at nucleotide 724, compared with the normal individual, who is homozygous A at this position. The individual with the R280C mutation is heterozygous T/C at nucleotide 982, compared with the normal individual, who is homozygous C at this position. The American Journal of Human Genetics 2000 67, 59-66DOI: (10.1086/302972) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 4 A, Segregation of the K194E mutation in family R. The presence of the K194E mutation was detected by SSCP analysis of a 284-bp PCR fragment encompassing exon 5. Normal individuals show two bands corresponding to the two DNA strands, whereas affected individuals show two doublets corresponding to the mutant and normal DNA strands. B, Segregation of the R280C mutation in family A. The presence of the R280C mutation was detected by its creation of a CCGCTG recognition site for the restriction enzyme MspA1-I. Digestion of a 245-bp PCR fragment encompassing exon 7 produces subfragments of 138 bp and 107 bp, in addition to the undigested 245-bp fragment, in affected individuals. In normal individuals, only the full-length 245-bp fragment is seen. In both cases, the mutation segregated with the disease in all family members tested. A representative section of each family is shown. The American Journal of Human Genetics 2000 67, 59-66DOI: (10.1086/302972) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 5 Ribbon diagram of the p63 DNA-binding domain, based on the structure of its homologue, p53. The narrow arrowheads denote side chains of the amino acid residues mutated in SHFM (K194 and R280 [red]), and the broad arrowheads denote residues mutated in EEC (R279 and R304 [green]). The American Journal of Human Genetics 2000 67, 59-66DOI: (10.1086/302972) Copyright © 2000 The American Society of Human Genetics Terms and Conditions