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

Research output: Contribution to journalArticle

Abstract

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately ∼75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.

Original languageEnglish
Pages (from-to)1776-1783
Number of pages8
JournalJournal of Investigative Dermatology
Volume126
Issue number8
DOIs
Publication statusPublished - Aug 2006

ASJC Scopus subject areas

  • Dermatology

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    Has, C., Wessagowit, V., Pascucci, M., Baer, C., Didona, B., Wilhelm, C., Pedicelli, C., Locatelli, A., Kohlhase, J., Ashton, G. H. S., Tadini, G., Zambruno, G., Bruckner-Tuderman, L., McGrath, J. A., & Castiglia, D. (2006). Molecular basis of Kindler syndrome in Italy: Novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene. Journal of Investigative Dermatology, 126(8), 1776-1783. https://doi.org/10.1038/sj.jid.5700339