P160L mutation in the Ca(2+) ATPase 2A domain in a patient with severe Darier disease

Area of Science:

• Genetics
• Molecular Biology
• Dermatology

Background:

• Darier disease (DD) is an autosomal dominant skin disorder.
• It is caused by mutations in the ATP2A2 gene, encoding the sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2).
• Mutations impact SERCA2 protein expression, degradation, and activity, affecting intracellular calcium regulation.

Observation:

• A patient with severe, sporadic Darier disease presented with inadequate response to acitretin and isotretinoin therapies.
• Genetic analysis revealed a heterozygous missense P160L mutation in the A domain of SERCA2.
• A polymorphism in intron 18 (2741 + 54 G --> A) was also identified.

Findings:

• The P160L mutation is located in the A domain of SERCA2, crucial for Ca(2+) translocation.
• This mutation likely impairs the protein's ability to maintain low intracellular calcium levels.
• The identified genetic variations may contribute to the severe phenotype and treatment resistance.

Implications:

• This case highlights a specific ATP2A2 mutation associated with severe Darier disease.
• Understanding the molecular basis of DD can guide the development of targeted therapies.
• Further research into SERCA2 function and calcium homeostasis is warranted for effective DD management.