Gene Variants May Drive Persistent Lesions in Darier Disease

Researchers looked at the complex molecular mechanisms of this rare skin condition. 

Persistent lesions in patients with Darier disease were associated with second-hit variants in the ATP2A2 gene, according to data from a new case series of 9 patients.

In a study published in JAMA Dermatology, Lihi Atzmony, MD, of Rabin Medical Center, Petach Tikva, Israel, and colleagues extracted DNA from areas of unaffected skin, transient lesional skin, persistent lesional skin, and blood from 9 adults with Darier disease (DD), a genetic skin disorder caused by heterozygous loss of function variants in the ATP2A2 gene and characterized by recurrent hyperkeratotic papules and plaques. These lesions may be mild or severe, and may be resistant to therapy.

Additional somatic changes might impact the persistence of lesions in DD patients, the researchers wrote. Whole exome sequencing of ATP2A2 revealed germline and second-hit somatic variations of ATP2A2 in 6 of 6 patients with 8 persistent lesions. In addition, deep sequencing revealed two somatic variants in the persistent cutaneous lesions that had been previously reported in DD patients. No second-hit variants in the ATP2A2 gene were identified in the 2 transient lesions or the 2 samples of normal skin.

The findings were limited by several factors including the disproportionate number of persistent lesions vs. transient lesions and the lack of data on the mono-allelic or bi-allelic nature of the second hits.

However, the results suggest an association between second-hit somatic ATP2A2 gene variants and persistent DD lesions, while environmental factors may drive development of transient lesions, the researchers concluded.

The study was supported in part by a grant from the LEO Foundation and a donation from the Trottner family. The researchers had no financial conflicts to disclose.

Source: Atzmony L et al. JAMA Dermatol. 2024 Mar 27. doi:10.1001/jamadermatol.2024.0152