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.