Molecular Basis of Kindler Syndrome in Italy: Novel and Recurrent Alu/Alu Recombination, Splice Site, Nonsense, and Frameshift Mutations in the KIND1.

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Presentation transcript:

Molecular Basis of Kindler Syndrome in Italy: Novel and Recurrent Alu/Alu Recombination, Splice Site, Nonsense, and Frameshift Mutations in the KIND1 Gene Cristina Has, Vesarat Wessagowit, Monica Pascucci, Corinna Baer, Biagio Didona, Christian Wilhelm, Cristina Pedicelli, Andrea Locatelli, Jürgen Kohlhase, Gabrielle H.S. Ashton, Gianluca Tadini, Giovanna Zambruno, Leena Bruckner-Tuderman, John A. McGrath, Daniele Castiglia Journal of Investigative Dermatology Volume 126, Issue 8, Pages 1776-1783 (August 2006) DOI: 10.1038/sj.jid.5700339 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical and skin biopsy findings in KS. (a) In patient 3, poikiloderma is evident on the neck and non-sun exposed skin behind the ear. (b) Cigarette paper-like atrophy is present on the dorsal aspect of the right hand of patient 4. (c) Ultrastructural analysis of KS skin showing reduplication of the lamina densa (red arrows) in patient 7, and (d) microdetachments (asterisks) within the lamina lucida in patient 8. (e) Linear labelling at the dermal epidermal junction for collagen VII in normal skin. (f) Markedly thickened, reticular, and patchy pattern of collagen VII labelling in patient 7. (g) Indirect immunofluorescence with antibodies to collagen XVII produced a linear staining in normal skin, but (h) an interrupted pattern in the skin of patient 4. Bars=(c and d) 0.85μm and (e–h) 20μm. Journal of Investigative Dermatology 2006 126, 1776-1783DOI: (10.1038/sj.jid.5700339) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Characterization of the 3.9kb deletion (g.70250_74168del) in KIND1. (a) Relative copy number of KIND1 gene exons 10 and 11 in the genomic DNA of patients 3 and 4 (P3, P4) and their parents (FP3, MP3, FP4, and MP4) measured by quantitative real-time PCR. (b, upper panel) Schematic representation of the KIND1 genomic region spanning exons 9–12. The 3.9kb deletion mutation is depicted by the dashed line. Primers qi9F and qi11R were used to amplify a 5.5kb region (hashed bar). (b, middle panel) A PCR product of ~1.5kb instead of the expected ~5.5kb amplicon was obtained with genomic DNA from patients 1 to 4 (P1–P4) and patients’ parents (MP1, MP2, MP3, FP1, FP3, and FP4). Mw, 100bp DNA ladder. (b, lower panel) Sequencing of the 1.5kb-PCR products showed identical deletion breakpoints within introns 9 and 11. The precise breakpoint lies somewhere in the 30bp between the 5′ variant base in intron 9 and the 3′ variant base in intron 11 (asterisks). Journal of Investigative Dermatology 2006 126, 1776-1783DOI: (10.1038/sj.jid.5700339) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Verification of the g.70250_74168del mutation in the affected families and mutation consequences at mRNA level. (a, upper panel) PCR-based diagnostic test for rapid screening of the deletion g.70250_74168del using primers a–c. Shaded region represents the 3.9kb deletion. (a, lower panel) A single band of 362bp was visualized in patients 1–3 (P1–P3), whereas two bands of 362 and 835bp were observed in patient 4 (P4) and in healthy carriers from these families (MP1, FP1, MP2, MP3, FP3, and FP4). The mother of patient 4 (MP4) and two unaffected controls (C1 and C2) generated a 835bp band (lanes 11–13). Mw, 100bp DNA ladder. (b) RT-PCR analysis of total RNA from patient 1 (P1) resulted in a unique PCR product of 796bp instead of the normal product of 1,028bp amplified from control cells (C). The 796-bp fragment corresponded to an aberrant out-of-frame transcript carrying the deletion of exon 10 and 11 (232bp). Mw, 100bp DNA ladder. A schematic representation of kindlin-1 structure with mutation consequences at protein level is also shown. PTC, premature termination codon. FERM, four-point one ezrin radixin moesin domain; PH, pleckstrin homology domain. Journal of Investigative Dermatology 2006 126, 1776-1783DOI: (10.1038/sj.jid.5700339) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Abundance of repetitive elements within introns 9 and 11 of KIND1. (a) Schematic representation of the genomic region spanning exons 9–12. Orientation and type of the repetitive sequence elements comprised in this region are indicated by arrowheads, the size of which is proportional to the length of the corresponding repeat. The two AluSx sequences involved in the 3.9kb deletion are indicated by gray arrowheads. (b) Sequence alignment between the AluSx repeats containing the deletion breakpoints. The sequences show 83% identity. The 30-bp sequence which identifies the precise site of the crossover event is highlighted by the gray box and the two 26-bp core sequences are depicted between the square brackets. The boldface type represents the sequence of the KIND1 mutated allele that results from the recombination event. Journal of Investigative Dermatology 2006 126, 1776-1783DOI: (10.1038/sj.jid.5700339) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions