FERMT1 promoter mutations in patients with Kindler syndrome.

[kindler syndrome]

Mutations in the FERMT 1 gene , encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS ), an autosomal recessive skin disorder with a phenotype comprising skin blistering , photosensitivity , progressive poikiloderma with extensive skin atrophy , and propensity to skin cancer . The FERMT 1 mutational spectrum comprises gross genomic deletions , splice site , nonsense , and frameshift mutations , which are scattered over the coding region spanning exon 2 -15 . We now report three KS families with mutations affecting the promoter region of FERMT 1 . Two of these mutations are large deletions (âˆ¼ 38 .0 and 1 .9 â€‰kb in size ) and one is a single nucleotide variant (c .-20 A >G ) within the 5 ' untranslated region (UTR ). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes . Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT 1 gene transcription and proved the causal role of the c .-20 A >G variant in reducing transcriptional activity .