Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other...

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Holoprosencephaly (HPE) is a congenital anomaly linked to reduced Sonic hedgehog (SHH) pathway activity.
• SHH signaling relies on receptors like PTCH1, CDON, BOC, and GAS1.
• The necessity of interactions among these SHH receptors was previously unknown.

Purpose of the Study:

• To investigate the role of CDON receptor interactions in SHH signaling.
• To identify mutations in CDON associated with human HPE.
• To determine how CDON mutations affect SHH pathway activity.

Main Methods:

• Identification and analysis of missense CDON mutations in human HPE patients.
• Cell-based signaling assays to assess SHH-dependent gene expression.
• Co-immunoprecipitation assays to study protein-protein interactions between CDON, PTCH1, GAS1, and SHH.

Main Results:

• Missense mutations in CDON were identified in human HPE.
• These CDON mutations impaired SHH-dependent gene expression in cell assays.
• Mutant CDON proteins showed reduced association with PTCH1 and GAS1, despite normal SHH binding.
• Impaired CDON-PTCH1 interaction correlated with reduced signaling activity.

Conclusions:

• CDON receptor interactions, particularly with PTCH1, are crucial for effective SHH signaling.
• Disruption of CDON-PTCH1 association is a mechanism underlying HPE.
• Understanding these interactions provides insight into HPE pathogenesis and potential therapeutic targets.