Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Microcephaly-capillary malformation (MIC-CAP) syndrome presents with severe microcephaly, cortical atrophy, epilepsy, developmental delay, and skin capillary malformations.
• The underlying genetic cause of MIC-CAP syndrome remained largely unknown.

Purpose of the Study:

• To identify the genetic basis of Microcephaly-capillary malformation (MIC-CAP) syndrome.
• To investigate the cellular and molecular mechanisms contributing to the syndrome's phenotype.

Main Methods:

• Whole-exome sequencing was performed on five patients diagnosed with MIC-CAP syndrome.
• Patient-derived cell lines were analyzed to assess STAMBP expression, protein aggregation, apoptosis, and pathway activation.

Main Results:

• Recessive mutations in STAMBP, encoding a deubiquitinating enzyme crucial for endocytosis, were identified as the cause of MIC-CAP syndrome.
• Reduced STAMBP expression led to ubiquitin-conjugated protein aggregate accumulation, increased apoptosis, and dysregulated RAS-MAPK and PI3K-AKT-mTOR signaling.
• These cellular defects correlate with the syndrome's neurological and vascular features.

Conclusions:

• Defects in the STAMBP deubiquitinating enzyme cause MIC-CAP syndrome, highlighting the role of endocytosis and protein degradation in neurodevelopment.
• Ubiquitin-conjugate aggregation and elevated apoptosis are implicated in the progressive neuronal loss observed in MIC-CAP syndrome.
• This study links a congenital disorder to a defective deubiquitinating protein, emphasizing the importance of endocytic pathway integrity.