Splice Site and Deletion Mutations in Keratin (KRT1 and KRT10) Genes: Unusual Phenotypic Alterations in Scandinavian Patients with Epidermolytic Hyperkeratosis

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Splice Site and Deletion Mutations in Keratin (KRT1 and KRT10) Genes: Unusual Phenotypic Alterations in Scandinavian Patients with Epidermolytic Hyperkeratosis Marie Virtanen, Anders Vahlquist Journal of Investigative Dermatology Volume 121, Issue 5, Pages 1013-1020 (November 2003) DOI: 10.1046/j.1523-1747.2003.12534.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Variable phenotype among patients with EHK. Clinical details are shown for five of the investigated patients: (a) PaA; (b) VL; (c) EK; (d) TA; (e) FJ. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Novel heterozygous single point mutations in KRT1 cause EHK with variable phenotype. (a) Restriction fragment length polymorphism analysis of the F191C mutation in K1 for patient PaA. The mutant allele gives rise to an 814 bp fragment due to the loss of the Tsp 509 I site. (b) Patient AS has a point mutation in codon 177, changing lysine to an asparagine residue (K177N). Automatic sequencing of exon 1 in KRT1 shows the reverse strand. M is a molecular size marker. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 A novel heterozygous single point mutation in KRT10 causes EHK with PPKD. (a) Manual sequencing of KRT10 (exon 6) in patient VL showed a point mutation in codon 453 changing a leucine residue to proline (L453P), residue 114 of the 2B helical domain. (b) Restriction fragment length polymorphism analysis of the L453P mutation in KRT10 using the restriction enzyme Bfa I. The mutant allele has a diagnostic 399 bp fragment due to loss of the Bfa I site. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Splice site mutations in KRT1 causing a mild EHK. (a) Patients OH and EK have a single heterozygous point mutation in the 5′ splice site of intron 1 in KRT1. Manual sequencing of genomic DNA from both patients and normal control (C) are shown. (b) PCR fragments covering exons 1–8 amplified from patients OH and EK yield two fragments (1061 bp and 995 bp) compared to the single fragment (1061 bp) from normal control cDNA. PCR fragments were separated on a 1.5% agarose gel. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Cloning of the mutant allele in KRT1 revealed a 22 amino acid deletion (H1+1A). (a) The mutant allele from patients OH and EK uses a cryptic splice site located 66 nucleotides upstream of the normal splice site. Automatic sequencing of the normal and mutant allele of KRT1 from EK is shown. (b) Schematic showing how the two different alleles (normal and mutant) are spliced in patients OH and EK. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 A 12 bp in-frame deletion in the H1 domain of KRT1 causes severe EHK. (a) PCR of exon 1 in KRT1 for patient PA gave rise to two fragments (199 bp and 187 bp). The fragments were separated on a 3% NuSieve plus 1% agarose gel. (b) The mutant allele of KRT1 from patient PA has a 12 bp deletion that removes residues 170–173 in the K1 protein. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 An insertion together with a deletion removes the whole of exon 6 affecting the 2B domain of K1. (a) A schematic showing the 442 bp deletion and the 214 bp insertion in KRT1. (b) Sequence analysis of exons 5, 6, and 7 of KRT1 cDNA. In the mutant allele, the sequence of exon 5 is followed by exon 7. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 A 6 bp deletion in the 1A domain of KRT10 causes a severe EHK phenotype. Automatic sequencing of the 1A domain of KRT10 (normal and mutant alleles). A 6 bp deletion removes residues 161 and 162 (leucine and aspartic acid) in the K10 protein. Journal of Investigative Dermatology 2003 121, 1013-1020DOI: (10.1046/j.1523-1747.2003.12534.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions