BOC is a modifier gene in holoprosencephaly.

Area of Science:

• Developmental biology
• Genetics
• Molecular biology

Background:

• Holoprosencephaly (HPE) is a common forebrain and midface developmental defect.
• Its etiology is complex, involving sonic hedgehog (SHH) pathway mutations but showing variable clinical presentation.
• Genetic or environmental modifiers are suspected but not identified.

Purpose of the Study:

• To identify genetic modifiers of Holoprosencephaly (HPE).
• To investigate the role of BOC, a SHH pathway coreceptor, as a potential HPE modifier.
• To characterize the functional impact of identified BOC variants in HPE patients.

Main Methods:

• Screening of Holoprosencephaly (HPE) patients for BOC gene variants.
• Functional assays using cell-based models to assess SHH signaling.
• Analysis of BOC protein variants for loss- or gain-of-function properties.

Main Results:

• Identification of missense BOC variants in patients with Holoprosencephaly (HPE).
• Demonstration that individual BOC variants exhibit either loss- or gain-of-function in SHH signaling.
• BOC variants modulate SHH pathway activity, consistent with a modifier role.

Conclusions:

• BOC variants represent the first identified low-frequency modifier genes contributing to Holoprosencephaly (HPE) variability.
• This finding adds a third variable, modifier genes, to the known factors influencing HPE etiology (SHH mutations and environmental factors).
• Understanding BOC's role can improve insights into HPE pathogenesis and potentially lead to targeted therapies.