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

[kindler syndrome]

Kindlin-1 is an epithelium-specific phosphoprotein and focal adhesion adaptor component . Mutations in the corresponding gene (KIND 1 ) 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 CaCo 2 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 .

Diseases
Validation

Diseases presenting "first months" symptom

alexander disease

gm1 gangliosidosis

harlequin ichthyosis

hirschsprung disease

homocystinuria without methylmalonic aciduria

kindler syndrome

lamellar ichthyosis

oligodontia

omenn syndrome

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