Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction.
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 beta 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.
Ussar
Siegfried
S
Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany.
Moser
Markus
M
Widmaier
Moritz
M
Rognoni
Emanuel
E
Harrer
Christian
C
Genzel-Boroviczeny
Orsolya
O
Fässler
Reinhard
R
D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D055786:Gene Knockout Techniques; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012873:Skin Diseases, Genetic / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology
D002352:Carrier Proteins; C534220:kindlin-1 protein, mouse