Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects

Area of Science:

• Neuroscience
• Gastroenterology
• Genetics

Background:

• Breakpoint cluster region (BCR) protein is implicated in leukemia and found in the central nervous system.
• BCR's role in neurological disorders and neural development is not fully understood.

Purpose of the Study:

• Investigate the physiological function of BCR in neural development within the gastrointestinal (GI) tract and brain.
• Determine the link between BCR mutations and pediatric intestinal obstruction.

Main Methods:

• Whole-exome sequencing to identify BCR mutations.
• CRISPR/Cas9 system to generate Bcr knockout mice (Bcr^-/-).
• GI transit assays and morphological analysis of neural plexuses and brain structures.

Main Results:

• A de novo BCR mutation was identified in an infant with pediatric intestinal pseudo-obstruction.
• Bcr^-/- mice showed growth retardation, impaired GI motility, and altered transit times.
• Bcr deficiency led to reduced neurons in GI plexuses and structural brain defects, particularly in the cortex.
• BCR depletion affected Rho GTPase expression in the mouse cortex.

Conclusions:

• BCR mutations are associated with intestinal obstruction in children.
• Loss of BCR function results in intestinal dysmotility and brain developmental defects.
• BCR may regulate neural development in the GI tract and brain via Rho GTPases.