Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction
| Autor: | Ussar, S., Moser, M., Widmaier, M., Rognoni, E., Harrer, C., Genzel-Boroviczeny, O., Fässler, R. |
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| Rok vydání: | 2008 |
| Předmět: |
lcsh:QH426-470
Dermatology/Pediatric Skin Diseases including Genetic Diseases Biochemistry Epithelium Cell Line Gene Knockout Techniques Mice Dermatology/Photodermatology and Skin Aging Cell Adhesion Animals Humans Intestinal Mucosa Genetics and Genomics/Genetics of Disease Skin Mice Knockout Gastroenterology and Hepatology/Inflammatory Bowel Disease integumentary system Skin Diseases Genetic Intestines lcsh:Genetics Cell Biology/Cell Adhesion Animals Newborn Genetics and Genomics/Disease Models Immunology/Immune Response Colitis Ulcerative Atrophy Carrier Proteins Research Article |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 4, Iss 12, p e1000289 (2008) |
| ISSN: | 1553-7404 |
| Popis: | 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. Author Summary Mutations in FERMT1, coding for the Kindlin-1 protein, cause Kindler Syndrome in humans, characterized by skin blistering, atrophy, and cancer. Recent reports showed that some Kindler Syndrome patients additionally suffer from ulcerative colitis. However, it is unknown whether this is caused by loss of Kindlin-1 or by unrelated abnormalities such as infections or additional mutations. We ablated the Fermt1 gene in mice to directly analyze the pathological consequences and the molecular mode of action of Kindlin-1. Kindlin-1–deficient mice develop a severe epidermal atrophy, but lack blisters. All mutant mice die shortly after birth from a dramatic, shear force-induced detachment of intestinal epithelial cells followed by a profound inflammation and organ destruction. The intestinal phenotype is very similar to, although more severe than, the one observed in Kindler Syndrome patients. In vitro studies revealed that impaired integrin activation, and thus impaired adhesion, to the extracellular matrix of the intestinal wall causes intestinal epithelial cell detachment. Therefore, we demonstrate that intestinal epithelial cells require adhesive function of integrins to resist the shear force applied by the stool. Furthermore, we provide evidence that the colitis associated with Kindler Syndrome is caused by a dysfunction of Kindlin-1 rather than by a Kindlin-1–independent event. |
| Databáze: | OpenAIRE |
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