Homozygous Mutations in the 5′ Region of the JUP Gene Result in Cutaneous Disease but Normal Heart Development in Children Rita M. Cabral, Lu Liu, Carol.

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Homozygous Mutations in the 5′ Region of the JUP Gene Result in Cutaneous Disease but Normal Heart Development in Children Rita M. Cabral, Lu Liu, Carol Hogan, Patricia J.C. Dopping-Hepenstal, Beatriz C. Winik, Raúl A. Asial, Richard Dobson, Charles A. Mein, Patricia A. Baselaga, Jemima E. Mellerio, Arti Nanda, Maria del Carmen Boente, David P. Kelsell, John A. McGrath, Andrew P. South Journal of Investigative Dermatology Volume 130, Issue 6, Pages 1543-1550 (June 2010) DOI: 10.1038/jid.2010.7 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features and immunohistochemistry. (a) Clinical features showing distinct phenotype of skin fragility, woolly hair, and palmoplantar keratoderma in affected patients from Argentina (top panel) and Kuwait (middle and lower panels). (b) Immunohistochemistry with monoclonal C- (PG5.1) and N-terminal (15F11) PG antibodies shows barely detectable PG in skin sections from patients A and K. (c) Immunohistochemistry shows normal adherens junction protein distribution in skin sections from control, parent A, and patient A (p.S24X). Scale bar=50μm. Journal of Investigative Dermatology 2010 130, 1543-1550DOI: (10.1038/jid.2010.7) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Two previously unreported homozygous mutations locate within the 5′ end of the JUP gene. (a) Electropherograms showing wild-type control and mutant nucleotide sequences in the second and third exons of JUP. Sequencing of patient A's DNA (upper right panel) reveals a homozygous transversion from cytosine to adenine at position 71, which changes a serine amino-acid codon, TCG, to a stop codon, TAG (c.71C>A, p.S24X). Sequencing of patient K's DNA (lower right panel) reveals a homozygous transition from guanine to adenine at position 468, which is predicted to abolish the natural splice donor of exon 3 (c.468G>A). Unaffected parents are heterozygous carriers of these mutations. (b) Automated splice site analyses predict the abolition of the natural splice donor of exon 3 after transition from guanine to adenine at position 468. (c) Schematic diagram of JUP exons 1–3 showing the site of the c.468G>A and p.S24X mutations. The native Kozak consensus sequence of JUP and three possible alternative translation start sites downstream of the p.S24X mutation are shown. The very next ATG at methionine 43 (M43) has the strongest Kozak sequence represented by an adenine at conserved position -3 and a guanine at conserved position +4, as observed for the native Kozak sequence (M1). (d) Schematic diagram showing the positions of p.S24X and c.468G>A mutations (boxed), as well as the two previously characterized mutations relative to the O-glycosylation site, the putative destruction box, and the armadillo repeats of the PG protein. Journal of Investigative Dermatology 2010 130, 1543-1550DOI: (10.1038/jid.2010.7) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 p.S24X mutation results in detectable mutant transcript and reduced levels of truncated protein in the skin. (a) Sequencing analysis of RT–PCR products generated with primers spanning exons 1–3 shows the presence of a mutant transcript in both parental and patient A samples, indicating that normal 5′ splicing is occurring. (b) Western blotting of skin proteins isolated from normal control (c), maternal (M), and patient (P) samples using a C-terminal PG antibody (PG5.1) shows low levels of a truncated protein in both maternal and patient samples. β-Actin was used as a loading control. (c) PGΔN42 is efficiently translated in human dermal fibroblasts. pBabe puro constructs containing vector alone (Vector), wild-type PG (WT), or p.S24X PG (S24X) were expressed in dermal fibroblasts, and PG reactive protein was detected by western blotting and an anti-PG antibody, PG5.1. NHK, normal human keratinocyte control. (d) Densitometry was used to calculate the amount of recombinant S24X protein in C (left) relative to wild type. Quantitative RT-PCR of cells expressing pBabe vectors from C reveals an increased level of p.S24X mRNA in dermal fibroblasts expressing S24X mutant PG compared with wild-type PG (right). This increase is reflected by the increased amount of protein shown: 4.2-fold more mRNA vs 5.2-fold more protein, respectively, indicating that the amount of PGΔN42 protein reflects the amount of mRNA relative to wild-type PG and that efficient translation takes place. Journal of Investigative Dermatology 2010 130, 1543-1550DOI: (10.1038/jid.2010.7) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions