Barrier activity of skin and internal barrier-forming epithelial linings ar
e conferred by a lipid-corneocyte structure (stratum corneum In skin). The
integrity of the corneocytes depends on the outer cornified envelope and is
essential for maintenance of barrier function. During epidermal developmen
t and differentiation, proteins are sequentially incorporated into the enve
lope via action of epidermal transglutaminases in a well documented process
. However, recent knockouts of major cornified envelope constituents have f
ailed to disrupt barrier function significantly, suggesting that additional
unidentified components are involved. We report a new gene cluster in the
epidermal differentiation complex at human 1q21 encoding a family of 18 pro
teins that are substrates for epidermal transglutaminases. These proteins i
ncorporate into the cornified envelope late in development and late in the
process of envelope maturation during epidermal differentiation. The genes
cluster within the epidermal differentiation complex according to expressio
n pattern, i.e., epidermally expressed proteins cluster together while prot
eins from internal barrier-forming epithelia also cluster. We propose that
these proteins modulate barrier activity over the surface of the animal, in
a manner analogous to that proposed for the well characterized cornified e
nvelope precursors, the small proline-rich proteins. To emphasize the incor
poration of these proteins late in envelope assembly, we call the human pro
teins late envelope proteins.