Abstract
Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1, -2, -3) that bind several β integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response.
Highlights
Kindler Syndrome (KS; OMIM:173650) is a rare, recessive genodermatosis caused by mutations in the FERMT1 gene (C20ORF42/KIND1) [1,2]
Recent reports showed that some Kindler Syndrome patients suffer from ulcerative colitis
It is unknown whether this is caused by loss of Kindlin-1 or by unrelated abnormalities such as infections or additional mutations
Summary
Kindler Syndrome (KS; OMIM:173650) is a rare, recessive genodermatosis caused by mutations in the FERMT1 gene (C20ORF42/KIND1) [1,2]. KS patients suffer from varying skin abnormalities that occur at distinct phases of their life [3]. Skin blisters develop and disappear after birth, followed by skin atrophy, pigmentation defects and skin cancer. The severity of the individual symptoms varies extensively among individual patients. FERMT1 mutations are distributed along the entire gene and can give rise to different truncated Kindlin-1 proteins [4]. The different courses of the KS cannot be linked to mutations within specific regions of the FERMT1 gene [3] suggesting that additional environmental and/or genetic factors contribute to the disease course
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