SERPINB8 – Exfoliative Ichthyosis

SERPINB8 has been implicated in an autosomal recessive form of exfoliative ichthyosis characterized by widespread epidermal peeling and impaired mechanical stability of intercellular adhesions. This association was first described through whole-exome sequencing in three unrelated families, each harboring homozygous loss-of-function variants in SERPINB8 (PMID:27476651). In a consanguineous Tunisian family, a frameshift variant c.947del (p.Lys316SerfsTer90) segregated with disease in all affected individuals and was absent in unaffected relatives, consistent with autosomal recessive inheritance (PMID:27476651). Two additional kindreds—one large Israeli family with a nonsense variant and a UAE pedigree with an initiation codon alteration—provided further genetic confirmation of the gene–disease link (PMID:27476651). Histological analysis of skin biopsies from homozygous individuals revealed keratinocyte disadhesion in the lower epidermis and reduced SERPINB8 protein levels compared to controls. In vitro, siRNA-mediated knockdown of SERPINB8 in human keratinocytes induced cell–cell adhesion defects under mechanical stress and upregulated desmosomal proteins, recapitulating the human phenotype (PMID:27476651). Mechanistically, loss of the reactive site loop—critical for SERPINB8–protease complex formation—underlies the impaired adhesion, supporting a loss-of-function disease mechanism.

Clinically, biallelic SERPINB8 testing should be considered in patients with early-onset exfoliative ichthyosis and mechanical skin fragility. Identification of pathogenic SERPINB8 variants enables definitive molecular diagnosis, informs recurrence risk in families, and may guide future therapies aimed at restoring protease-inhibitor balance in the epidermis.

References

• American Journal of Human Genetics • 2016 • Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions PMID:27476651

Evidence Based Scoring (AI generated)