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Genotype–Phenotype Correlation in Recessive Dystrophic Epidermolysis Bullosa: When Missense Doesn't Make Sense  Vesarat Wessagowit, Soo-Chan Kim, Se Woong.

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Presentation on theme: "Genotype–Phenotype Correlation in Recessive Dystrophic Epidermolysis Bullosa: When Missense Doesn't Make Sense  Vesarat Wessagowit, Soo-Chan Kim, Se Woong."— Presentation transcript:

1 Genotype–Phenotype Correlation in Recessive Dystrophic Epidermolysis Bullosa: When Missense Doesn't Make Sense  Vesarat Wessagowit, Soo-Chan Kim, Se Woong Oh, John A. McGrath  Journal of Investigative Dermatology  Volume 124, Issue 4, Pages (April 2005) DOI: /j X x Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 Clinicopathological assessment is consistent with either localized recessive dystrophic epidermolysis bullosa or de novo dominant disease. The clinical features include (A) dystrophic or rudimentary toenails and (B) blisters, erosions, and inflammatory papules on the shins. Indirect immunofluorescent staining with LH7.2 monoclonal antibody (NC-1 domain of type VII collagen) shows bright linear labeling at the dermal–epidermal junction in the patient's skin (C) of intensity and distribution similar to normal control skin (D). Scale bar=40 μm. Journal of Investigative Dermatology  , DOI: ( /j X x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Nucleotide sequencing of the patient's genomic DNA reveals compound heterozygosity for two single nucleotide substitutions in COL7A1. (A) There is a heterozygous 341G>T transition in exon 3 (maternally inherited), which is predicted to change a glycine residue to valine (G114V). (B) There is also a heterozygous 5797C>T transition in exon 70 (paternally inherited), which is predicted to change an arginine residue to a stop codon (R1933X). The mutation 341G>T, however, is also predicted to activate a new strong cryptic site, with the Ri value increasing from 0.0 bits (C) to 8.2 bits (D) at this position, whereas the natural donor site remains unchanged at 6.6 bits (E). This suggests cryptic splicing induced by the substitution 341G>T. No such changes were evident in assessing 5797C>T. Journal of Investigative Dermatology  , DOI: ( /j X x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Direct sequencing of complementary DNA (cDNA) from the patient's and mother's skin confirms cryptic splicing in exon 3. (A) PCR of cDNA between nucleotide positions 257 and 558 reveals a single 302 bp band in a control (C) and two bands in the proband (Pt) and mother (M), one of which is 302 bp and the other 215 bp, i.e., 87 bp shorter. (B) Direct sequencing of the lower band reveals an 87 bp deletion between nucleotides 340 and 426. (C) Schematic diagram of the NC-1 domain of COL7A1 messenger RNA showing the position of the 29 amino acid deletion within the CMP domain, upstream from the epitope for the LH7.2 antibody in the middle of the FN III-like repeats. SP, signal peptide; CMP, domain with homology to cartilage matrix protein; FN III, fibronectin-type III-like motifs; VWF-A, von Willebrand factor-type A-like domain; C/P, cysteine- and proline-rich domain (Christiano et al, 1992). Journal of Investigative Dermatology  , DOI: ( /j X x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

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