Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement.

Department of Dermatology, Paracelsus Private Medical University of Salzburg, Salzburg, Austria.
Archives of Dermatology (Impact Factor: 4.31). 01/2007; 142(12):1619-24. DOI: 10.1001/archderm.142.12.1619
Source: PubMed

ABSTRACT Kindler syndrome (online Mendelian Inheritance in Man No. 173650) is an autosomal recessive genodermatosis characterized by acral trauma-induced blistering that improves with age and by progressive poikiloderma in later life. Other clinical features include photosensitivity, webbing of the fingers and toes, nail dystrophy, periodontal disease, and mucosal alterations. Aside from esophageal or anal stenosis, gastrointestinal tract involvement seems to be rare in Kindler syndrome. Recently, mutations in the KIND1 gene that encodes for the membrane-associated protein kindlin-1 have been identified. Kindlin-1 links the actin cytoskeleton to the extracellular matrix and is supposed to have cell-signaling functions owing to different functional domains. In particular, a domain with high homology to 4.1/ezrin/radixin/moesin (FERM) proteins is closely related to the sequences of talin that mediate integrin binding and therefore may play a role in integrin-dependent processes such as cell growth, differentiation, and apoptosis.
Complete loss of this multifunctional protein in our patient with Kindler syndrome resulted in severe gastrointestinal tract involvement with hemorrhagic colitis. Mucosa of the descending and sigmoid colon and the rectum showed erosions and ulcers with pseudomembranous alterations of an overall highly vulnerable mucosa. Mutation analysis revealed a homozygous status for the novel mutation 20/21delTT in exon 2 of the KIND1 gene resulting in a preterminal stop codon creating a nonfunctional peptide 17 amino acids in length.
Because of our experience with this and another patient, we propose that gastrointestinal tract involvement should be looked at more frequently in Kindler syndrome.

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    ABSTRACT: From a forward genetic screen for epidermal defects in zebrafish, we identified a loss-of-function mutation in Kindlin-1, an essential regulator of integrin function. The mutation generates a premature stop codon, deleting the integrin-binding site. The mutant zebrafish develop cell-matrix and cell-cell adhesion defects in the basal epidermis leading to progressive fin rupturing, and was therefore designated rupturing-of-fins (rof). Similar defects were observed in the epidermis of Kindler syndrome patients, carrying a loss-of-function mutation in kindlin-1. Mutational analysis and rescue experiments in zebrafish revealed that residues K610, W612, and I647 in the F3 domain are essential for Kindlin-1 function in vivo, and that Kindlin-2 can functionally compensate for the loss of Kindlin-1. The fin phenotype of rof/kindlin-1 mutants resembles that of badfin mutants, carrying a mutation in Integrin α3. We show here that this mutation impairs the biosynthesis of integrin α3β1, and causes cell-matrix and cell-cell defects in vivo. Whereas both Integrin-linked kinase and Kindlin-1 cooperate with Integrin α3β1 to resist trauma-induced epidermal defects, Kindlin-1 and Ilk surprisingly do not act synergistically but in parallel. Thus, the rof/kindlin-1 mutant zebrafish provides a unique model system to study epidermal adhesion mechanisms in vivo.Journal of Investigative Dermatology accepted article preview online, 2 April 2013; doi:10.1038/jid.2013.154.
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