294 Dermcidin: a new player in a familiar case of Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent 40% of the total HS cases and show an autosomal dominant mode of inheritance of the disease. By studying an HS family we found a rare DCD gene frameshift insertion in heterozygosis (rs538180888); DCD encodes for dermcidin (DCD), an antimicrobial peptide (AMP) produced by sweat glands. AMPs are considered key effectors of cutaneous innate immune responses and are normally constitutively expressed in human epithelia by keratinocytes, neutrophils, sebocytes or sweat glands; deregulation in the expression of AMPs, including DCD, may be associated with the etiology of inflammatory skin diseases, such as HS. Considering that the expression of DCD is specifically limited to sweat, DCD levels were measured in patients and healthy controls. We observed a significant reduction of DCD levels in the patients’ sweat when compared to the controls. We showed in silico that the identified frameshift variant disrupts the ORF of DCD and results in a 33 amino acid peptide with a completely altered sequence affecting both the N-term and the C-term partitions, hence impairing the antimicrobial activity of DCD. We confirmed this altered activity by observing lack of bactericidal effect on planktonic S. aureus, S. epidermidis and S. lugdunensis; moreover, mutated DCD was not able to limit biofilm formation or to eradicate pre-formed biofilm by S. aureus. Taken together, our findings obtained by genetic analysis on familial HS highlight a novel potential actor playing a role in HS etio-pathogenesis, since the absence of DCD will lead to bacterial biofilm formation and possible dysbiosis.