Researchers may have uncovered the mechanisms behind the development of aplasia cutis congenita, according to a novel study published by Raymundo et al in The Journal of Clinical Investigation. Previous studies have shown that KCTD1 and KCTD15 mutations—both of which may be responsible for aplasia cutis congenita—can lead to ectodermal abnormalities and kidney fibrosis, as well as cardiac outflow tract abnormalities, respectively. In the novel study, the researchers modeled the mutations using mouse models and cells. They discovered that KCTD1 proteins were necessary for cardiac outflow tract development, whereas KCTD15 proteins regulated distal nephron function. Both proteins were capable of creating multimeric complexes that could compensate for the other’s losses. KCTD1 and KCTD15 mutations were found to be dominant-negative, potentially causing a lack of protein function. Further, combined inactivation of KCTD1 and KCTD15 in the neural crest cells of mice resulted in aplasia cutis congenita, demonstrating that the condition may be linked to a secondary consequence of impaired cranial neural crest cells that contribute to the development of midline cranial suture cells expressing keratinocyte-promoting growth factors. The researchers hope their new findings may inspire novel strategies to prevent the development of aplasia cutis congenita. In a companion press release on the findings from Massachusetts General Hospital, the study authors concluded: “We solved a centuries-old enigma, which allows us now to explain why this congenital skin disease affects the midline scalp but not other areas of the skin … [and uncover] fundamental new insights into mechanisms that orchestrate skin and skin appendage formation.”
January 24, 2024