Role of Sp1 response element in transcription of the human transglutaminase 1 gene

This study addresses the contribution of an Sp1 response element in the pro ximal promoter of the transglutaminase 1 gene to transcription in normal ep idermis and in a case of lamellar ichthyosis lacking transglutaminase 1 act ivity. The latter exhibited an Sp1 promoter mutation previously hypothesize d to suppress transcription. In this study, several experiments indicated t hat the native Sp1 response element was functional, but it had only a small influence on transcription, and the previously observed mutation had no ef fect. These experiments involved mobility shift assays and transfections of promoter constructs in which the Sp1 site was mutated or lacking altogethe r. In addition the proximal 1.6 kb of the promoter from the affected indivi dual was as active in transfections as the promoter from unaffected individ uals. A search for sequence alterations in mRNA transcribed in keratinocyte s from the patient revealed a novel single base mutation in codon 661 of th e transglutaminase coding region predicted to result in premature terminati on of protein translation. The presence of this mutation in parental genomi c DNA was confirmed by restriction digestion. Thus the lamellar ichthyosis phenotype in this case is likely attributable to a novel non-sense mutation in the coding region leading to reduced transglutaminase 1 mRNA levels rat her than mutation of the Sp1 site.