Chronic colitis due to an epithelial barrier defect: the role of kindlin‐1 isoforms

Abstract

Kindlin-1 is an epithelium-specific phosphoprotein and focal adhesion adaptor component. Mutations in the corresponding gene (KIND1) cause Kindler syndrome (KS), which is manifested by skin blistering, poikiloderma, photosensitivity and carcinogenesis. Some patients also exhibit gastrointestinal symptoms, but it has remained unclear whether these represent a feature of Kindler syndrome or a coincidence. We examined kindlin-1 in human gastrointestinal epithelia and showed that it is involved in the aetiopathology of Kindler syndrome-associated colitis. Kindlin-1 expression was assessed by indirect immunofluorescence, western blot and RT-PCR. Kindlin-1 is expressed in oral mucosa, colon and rectum. Both the full-length 74 kDa kindlin-1 protein and a 43 kDa isoform were detected in CaCo2 cells, the latter resulting from alternative splicing. In the first months of life, patients (homozygous for null mutations) had severe intestinal involvement with haemorrhagic diarrhoea and showed morphological features of severe ulcerative colitis. Later in childhood, histopathology demonstrated focal detachment of the epithelium in all segments of the colon, chronic inflammation and mucosal atrophy. These findings define an intestinal phenotype for Kindler syndrome as a consequence of a primary epithelial barrier defect. The different clinical intestinal manifestations in Kindler syndrome patients may be explained by partial functional compensation of kindlin-1 deficiency by the intestinal isoform or by the presence of truncated mutant kindlin-1.

The kindlin family: functions, signaling properties and implications for human disease

“…Although KS has initially been described as a skin disorder, KS patients also suffer from an ulcerative colitis-like condition (Kern et al, 2007;Ussar et al, 2008). The colitis-like condition is much more severe in mice compared with humans; in the latter symptoms are usually mild and the condition is rarely lethal.…”

Induction of phenotype modifying cytokines by FERMT1 mutations

“…Cell lines derived from normal human keratinocytes (NK) and KS patient 4 (KSK), as well as primary keratinocytes of KS patients 1 and 8, and of control individuals have been characterized previously (Has, et al, 2009;Has, et al, 2008a;Kern, et al, 2007).…”

“…Their age, mutations and phenotypic features indicating fibrosis in skin and mucous membranes are summarized in Table 1. Patients 1 -4, 6 -8 have been described in detail before (Has, et al, 2008a;Has, et al, 2008b;Herz, et al, 2006;Kern, et al, 2007;Mansur, et al, 2007). Importantly, at the time of presentation and skin biopsy, none had blisters, wounds, or skin fragility.…”

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

“…Subsequently, we observed a similar pattern in P2. Notably, both patients had FERMT1 duplication insertion mutations, which led to frame shifts, premature termination codons, and loss of full-length kindlin-1, as demonstrated by immunoblotting of keratinocyte lysates (10). A systematic review of 24 additional KS patients revealed that all individuals harboring duplicating insertions (P3-P6; Table 1) exhibited the same skin pattern ( Supplemental Figures 1 and 2; supplemental material available online with this article; doi:10.1172/JCI61976DS1).…”