KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis

Area of Science:

• Developmental biology
• Genetics
• Dermatology

Background:

• Aplasia cutis congenita (ACC) is a congenital scalp defect, often attributed to keratinocyte issues.
• The specific cause and midline localization of ACC remain unclear.
• Mutations in KCTD1 and KCTD15 are linked to ACC and other developmental abnormalities.

Purpose of the Study:

• To investigate the underlying cause of Aplasia cutis congenita (ACC).
• To elucidate the roles of KCTD1 and KCTD15 in development.
• To determine the cell type responsible for ACC pathogenesis.

Main Methods:

• Analysis of KCTD1 and KCTD15 complex formation and function.
• Investigating the effects of KCTD1/KCTD15 inactivation in keratinocytes and neural crest cells.
• Correlating findings with clinical observations in patients with KCTD1/KCTD15 mutations.

Main Results:

• KCTD1 and KCTD15 form functional complexes that can compensate for each other.
• Disease-associated mutations act in a dominant-negative manner, impairing complex function.
• Inactivation in keratinocytes caused skin appendage defects, but not ACC.
• Inactivation in neural crest cells led to ACC and midline skull defects.

Conclusions:

• ACC is a neurocristopathy, originating from impaired cranial neural crest cells, not a primary keratinocyte defect.
• KCTD1/KCTD15 complexes are crucial for ectodermal and neural crest cell development.
• Findings explain clinical variability in KCTD1/KCTD15-related disorders.