FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.

Area of Science:

• Neurodevelopmental disorders
• Molecular biology
• Genetics

Background:

• Pontocerebellar hypoplasia (PCH) comprises rare neurodevelopmental disorders with few treatment options.
• Mutations in WDR11, part of the FAM91A1 complex, are linked to PCH-like symptoms, but causality remains unproven.

Purpose of the Study:

• To investigate the role of FAM91A1 in PCH pathogenesis.
• To elucidate the molecular interaction between FAM91A1 and TBC1D23, an established PCH gene.
• To explore the functional consequences of this interaction on protein trafficking and axonal development.

Main Methods:

• Depletion of FAM91A1 in zebrafish to observe developmental defects.
• Co-immunoprecipitation assays to confirm interaction between FAM91A1 and TBC1D23.
• Crystallography to determine the structural basis of the FAM91A1-TBC1D23 complex.
• Analysis of endosome-to-Golgi trafficking of KIAA0319L.

Main Results:

• FAM91A1 depletion in zebrafish caused developmental defects mirroring those seen in TBC1D23-deficient models.
• FAM91A1 and TBC1D23 were shown to directly interact and cooperate in regulating KIAA0319L trafficking.
• The crystal structure revealed TBC1D23 binding to FAM91A1 via a Z-shaped conformation.
• The interaction interface can predict the PCH risk associated with TBC1D23 mutations.

Conclusions:

• The study provides a molecular mechanism for FAM91A1 and TBC1D23 interaction, highlighting their cooperative role in endosome-to-Golgi trafficking.
• Disrupted endosomal trafficking is implicated as a common pathogenic pathway in multiple PCH subtypes.
• This research offers potential avenues for predicting PCH risk and developing therapeutic strategies.