LORICRIN – Honeycomb Palmoplantar Keratoderma with Ichthyosis

Loricrin keratoderma is a rare autosomal dominant palmoplantar keratoderma characterized by honeycomb palmoplantar hyperkeratosis and diffuse ichthyosiform dermatosis. Clinical diagnosis hinges on these two hallmark features, and genetic analysis has implicated heterozygous LORICRIN mutations.

Two unrelated pedigrees comprising ≥3 affected individuals demonstrated autosomal dominant transmission of LORICRIN variants (e.g., 730insG and c.323G>C (p.Gly108Ala)) (PMID:16403113, PMID:35346558). Segregation of c.323G>C (p.Gly108Ala) in a Chinese Han family confirmed father-to-son inheritance (one informative meiosis) (PMID:35346558).

Pathogenic variants primarily consist of frameshifting insertions producing C-terminal extensions (for example, 730insG elongating loricrin by 22 amino acids) and missense changes such as c.323G>C (p.Gly108Ala).

Pyrosequencing of an affected individual revealed equal expression of mutant and wild-type LORICRIN alleles, strengthening a gain-of-function model (PMID:16403113). Confocal microscopy of HaCaT keratinocytes expressing c.323G>C (p.Gly108Ala) showed aberrant cytoplasmic accumulation of the mutant protein versus wild-type distribution (PMID:35346558).

Insertional mutations, such as a T insertion at codon 209 causing a 107-amino-acid frameshift, disrupt transglutaminase-mediated cross-linking in a Vohwinkel model (PMID:9764857). An inducible HaCaT cell system expressing a Vohwinkel-associated mutant demonstrated nine-fold increased Akt kinase activity and phosphorylation of ERK1/2, VEGFR2, and Stat3, with Stat3 binding to the VEGF promoter, linking LORICRIN mutations to keratinocyte hyperproliferation (PMID:20236940).

Collectively, three pedigrees, segregation data, and concordant functional studies provide strong evidence that heterozygous gain-of-function LORICRIN variants cause loricrin keratoderma. There is no support for haploinsufficiency as a disease mechanism. Genetic testing for dominant LORICRIN mutations is clinically informative and may guide future targeted interventions.

Key Take-home: Gain-of-function LORICRIN mutations underlie autosomal dominant honeycomb palmoplantar keratoderma with ichthyosis, supporting their use in diagnostic testing and therapeutic research.

References

• The British journal of dermatology • 2006 • Towards characterization of palmoplantar keratoderma caused by gain-of-function mutation in loricrin: analysis of a family and review of the literature. PMID:16403113
• Journal of dermatological science • 2022 • The c.323G>C mutation in LORICRIN causes new-found late-onset autosomal dominant loricrin keratoderma in a Chinese Han Pedigree. PMID:35346558
• The Journal of investigative dermatology • 1998 • A novel insertional mutation in loricrin in Vohwinkel's Keratoderma. PMID:9764857
• The Journal of biological chemistry • 2010 • Activation of vascular endothelial growth factor receptor 2 in a cellular model of loricrin keratoderma. PMID:20236940

Evidence Based Scoring (AI generated)