PathwayType: signaling

Organ: skin

Description: Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Pathway is built manually using published studies.

Notes: Headnote: Ichthyosis is a family of mostly genetic disorders with dry, scaly and thickened skin. Harlequin ichthyosis is the most phenotypically severe inherited ichthyosis. Skin development is altered in utero. Hyperkeratosis of the hair canal occurs in the second trimester and characteristic ultrastructural abnormalities including abnormal lamellar granules are present in the affected fetal epidermis. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis. Signaling description: Ceramide activates PPAR delta, leading to stimulation of the transmembrane transporter ABCA12 production. ABCA12 is important for the transport of lipids, as well as regulation of protein synthesis in the developing skin layer. In the stratum corneum, ABCA12 transports glucosylceramides into epidermal lamellar bodies. In keratinizing keratinocytes of the upper epidermis, ABCA12 is responsible for the lamellar granule lipid transport. The role of ABCA12 defects in the pathogenesis of harlequin ichthyosis is depicted on the pathway. Outcome effects: Deficient ABCA12 function causes lipid transport disruption in lamellar bodies, and therefore leads to a decrease in intercellular lipid levels in the stratum corneum. ABCA12 mutations have been associated with defects in the distribution and transport of glycosylceramide, as well as decreased levels of hydroxyceramides, one of the main components in the lipid barrier in the intercellular spaces. The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier. It might also be due to the lack of desquamation of the corneocytes, which could be caused by defects in the transport of certain proteases, such as kallikrein 5 and cathepsin D. Increased amounts of cellular glucosylceramide and gangliosides induce apoptosis in keratinocytes. Animal data: CTSD, KLK5 and glucosylceramide are highlighted in blue illustrating the protective skin barrier disruption in the stratum corneum. Gangliosides and glucosylceramide with red highlights have increased accumulation in harlequin ichthyosis. Animal data: not shown Mutated proteins: ABCA12 gene mutated in harlequin ichthyosis is in white-out style.

PMID: 24055887

NodeType: Pathway

PMID: 26945532

Pathway_Author: V. Sobolev ORCID:0000-0003-4779-156X

Organ_System: integumentary system

PMID: 23562412

Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-469a3717-7be0-49e4-af92-f78bd39c6d73

PMID: 18957418

CellType: keratinocyte

Source: Diseases

PMID: 23954554

urn:agi-pathway:uuid-469a3717-7be0-49e4-af92-f78bd39c6d73