Molecular Characterization of Autosomal Recessive Congenital Ichthyosis

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous group of non-syndromic cornification disorders characterized primarily by generalized hyperkeratotic epidermal scales with or without erythroderma. So far, pathogenic variants in fourteen genes have been associated with ARCI most of which perturb lipid metabolism and localization during cornification, thereby disrupting the lipid envelope and thus barrier function. Research is in progress to reduce or treat the disease manifestations in affected individuals by enzyme replacement therapy and gene therapy. Moreover, gene expression studies and histopathological studies have been performed to discover more effective drug targets. However, a more precise genotype to phenotype correlation and a greater understanding of the pathophysiology would aid in developing more specific therapies. Therefore, the necessity is to elucidate the link between a defective gene and the resulting difference in expression of proteins in epidermis. In the current study whole exome sequencing (WES), Sanger sequencing and mass spectrometry were used to investigate four consanguineous Pakistani families (A, B, C, and D) affected with ARCI. WES identified a frameshift mutation c.364dupA (p.T122IfsX3) in SDR9C7 in family A, a nonsense mutation c.762C>G (p.Tyr254*) in PNPLA1 in family B, a missense mutation c.944G>A (p.R315H) in TGM1 in family C, and a missense mutation c.424 (p.R142C) in TGM1 in family D. Mass spectrometry of purified proteins isolated from epidermal corneocytes samples of the affected individuals confirmed the deleterious effects of the identified mutations. Combinatorial protein analysis of the three groups (PNPLA1, SDR9C7, and TGM1) identified common 20 proteins with altered expression in all the disease groups indicating their central role in ARCI pathology. Furthermore, a proteomic spectrum specific for each type of ARCI was also acquired. In conclusion, four families affected with ARCI were identified with mutations in SDR9C7, PNPLA1, and TGM1 along with the proteomic profiles that could aid in the genetic counseling and prenatal diagnosis of the families as well as devising improved diagnostic and therapeutic approaches for ARCI.