CDSN

Corneodesmosin (CDSN) is a keratinocyte adhesion glycoprotein of the corneodesmosome that maintains cell-cell cohesion in the upper epidermis and is required for normal scalp hair follicle physiology (PMID:12754508). Loss of corneodesmosin function—through nonsense or frameshift mutations, large genomic deletions, or expression of stable but nonfunctional truncated protein—abrogates epidermal integrity and produces peeling skin syndrome type B, with impaired upper-epidermal adhesion and barrier disruption (PMID:22146835, PMID:23957618, PMID:24116970); complete deletion of CDSN alone is sufficient for this phenotype even when neighboring PSORS1-region genes are co-deleted (PMID:24372652). Distinct truncating mutations instead cause hypotrichosis simplex of the scalp, where truncated corneodesmosin aggregates accumulate around hair follicles (PMID:12754508). Genetic epistasis establishes that the desquamation-initiating serine protease KLK5 cannot compensate for corneodesmosin loss; its removal instead aggravates corneodesmosome ultrastructural defects and barrier permeability as other proteases assume increased activity (PMID:40943523). Downstream of corneodesmosin deficiency, barrier disruption drives an inflammatory response in which Th2 cytokine (IL-4/IL-13) and JAK1 signaling are implicated (PMID:39377561).

1. 2003 High

   Established corneodesmosin as a keratinocyte adhesion molecule with a role in scalp follicle physiology by linking its loss to a defined human phenotype.

   Evidence DNA sequencing of affected families with immunohistochemical detection of truncated CDSN aggregates in scalp biopsies

   PMID:12754508

   Open questions at the time

   • Molecular basis of adhesion (binding partners within the corneodesmosome) not defined
   • Why truncated protein aggregates rather than degrades unaddressed
2. 2011 Medium

   Connected biallelic loss-of-function to generalized peeling skin syndrome, framing corneodesmosin deficiency as a cause of upper-epidermal adhesion failure and barrier-driven inflammation.

   Evidence PCR and direct sequencing identifying a homozygous frameshift, with clinical phenotyping

   PMID:22146835

   Open questions at the time

   • Adhesion and barrier defects inferred clinically, not measured directly
   • Single family, single sequencing method
3. 2013 Medium

   Distinguished two routes to disease—stable truncated protein versus complete absence—by showing a nonsense mutation yields a stable but nonfunctional 16-kDa fragment while a 59-kb Alu-mediated deletion abolishes expression entirely.

   Evidence Sequencing plus Western blot/IHC/qPCR for the truncation allele, and breakpoint sequencing/QMPSF/haplotyping for the deletion

   PMID:23957618 PMID:24116970

   Open questions at the time

   • Direct functional assay of the truncated protein's residual adhesion activity absent
   • Contribution of co-deleted flanking genes not yet excluded at this stage
4. 2014 Medium

   Demonstrated that loss of CDSN alone is sufficient for peeling skin syndrome, isolating it from neighboring PSORS1 genes, and provided ultrastructural evidence that mutant protein shortens and sparsifies corneodesmosomes.

   Evidence IHC/PCR/QMPSF/CGH array on a complete-deletion case showing no extra phenotype from co-deleted genes; electron microscopy with morphometry on a missense case

   PMID:24372652 PMID:25473393

   Open questions at the time

   • Mechanism by which corneodesmosin sets corneodesmosome size unresolved
   • Missense-allele finding is a single low-confidence case without functional protein assay
5. 2024 Low

   Linked corneodesmosin deficiency to a specific inflammatory axis by showing Th2 cytokine overexpression and clinical benefit from JAK1 inhibition.

   Evidence Whole exome sequencing, IHC for CDSN and IL-4/IL-13, and clinical response to upadacitinib in a single PSS1 patient

   PMID:39377561

   Open questions at the time

   • Single case with IHC-based and therapeutic-response inference, not mechanistic proof
   • Causal chain from barrier loss to Th2/JAK1 activation not established
6. 2025 High

   Resolved whether desquamation proteases compensate for corneodesmosin loss, showing via genetic epistasis that removing KLK5 worsens rather than rescues the phenotype.

   Evidence shRNA CDSN knockdown in human epidermal equivalents and Cdsn/Klk5 double-knockout mice with ultrastructural and barrier permeability readouts

   PMID:40943523

   Open questions at the time

   • Identity of the compensating proteases that gain activity in KLK5 absence not determined
   • Single-lab study; direct biochemical substrate relationships not mapped

• The direct molecular binding partners of corneodesmosin within the corneodesmosome and the biochemical basis of its adhesive function remain undefined.
• No identified direct protein interactor or structural model in the corpus
• Proteases responsible for normal corneodesmosin turnover not enumerated