GIT1 loss of function causes a recognizable syndromic neurodevelopmental disorder.

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Cell Biology

Background:

• G-protein-coupled receptor kinase-interacting protein 1 (GIT1) is a scaffold protein regulating cytoskeleton dynamics and cell signaling.
• Loss of Git1 function in mice leads to microcephaly and neurodevelopmental deficits.
• No definitive link between GIT1 variants and human disease had been established.

Purpose of the Study:

• To investigate the genetic basis of a syndromic neurodevelopmental disorder.
• To establish a causal link between GIT1 variants and human disease.
• To elucidate the functional consequences of GIT1 loss-of-function in neurodevelopment.

Main Methods:

• Combined genomic analysis including linkage analysis and exome sequencing.
• In vitro functional studies using patient-derived fibroblasts.
• In vivo validation using a zebrafish git1 knockdown model.

Main Results:

• Identified biallelic GIT1 variants causing transcript processing defects or premature termination in nine affected individuals from three families.
• Phenotype included microcephaly, brain MRI anomalies, developmental delay/intellectual disability, distinct facial features, and growth restriction.
• Functional studies confirmed GIT1 loss-of-function disrupts actin cytoskeleton dynamics, cell spreading, and focal adhesion formation, linked to reduced RAC1 activation.

Conclusions:

• Biallelic GIT1 variants cause a syndromic neurodevelopmental disorder in humans.
• GIT1 is essential for normal brain development, neuronal cell size, and cognitive function.
• The findings highlight GIT1 as a critical gene for human neurodevelopment and cognitive processes.