Proteomic manifestations of genetic defects in autosomal recessive congenital ichthyosis

Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Present work investigates the degree to which the departure from normal of ichthyosis corneocytes on the skin surface depends upon the basic defect as judged by proteomic profiling. Analyzing autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1 revealed that profiles of PNPLA1 samples displayed the greatest degree of departure from normal control epidermis, with SDR9C7 samples nearly as divergent, and TGM1 the least divergent. Although the profiles were distinctive, each displaying a set of altered protein levels, they exhibited alterations in 20 proteins in common, of which 15 were expressed consistently at higher and 5 at lower levels. Departure from the normal profile was examined at three different anatomic sites (forearm, forehead, leg). Reflecting that the normal protein profile differed at these sites, comparing profiles from afflicted subjects revealed that the degree of alteration in profile was site-dependent. These results suggest proteomic profiling can provide a quantitative measure of departure from the normal state of epidermis. Further development may help characterize consequences of the genetic defects, including perturbation of signaling pathways, and supplement visual evaluation of treatment. Significance: ARCI are rare cornification disorders caused by mutations in at least 14 different genes leading to perturbed metabolism and organization of constituent biomolecules of cornified envelopes. The phenotypic manifestations of the disorder vary among individuals with the same as well as different genetic defects and even at different anatomic sites within the same individual. The present study investigates the proteomic disturbances at three anatomic sites in patients carrying mutations in three different genes. Our findings provide a basis for elucidating genotype to proteome relationships for ARCI, further investigation of which may help to delineate the underlying pathways as well as to identify new drug targets.