RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Polymorphisms in RSRC1 are linked to altered brain function in schizophrenia.
• RSRC1 is a member of the serine and arginine-rich protein family.

Purpose of the Study:

• To investigate the genetic basis of an autosomal recessive syndrome.
• To elucidate the role of RSRC1 in neurodevelopment and associated disorders.

Main Methods:

• Homozygosity mapping and whole exome sequencing.
• Short hairpin RNA (shRNA)-mediated gene silencing and overexpression in cell lines.
• Transcriptome profiling and protein-protein interaction network modeling.
• Induced pluripotent stem cell differentiation and neural progenitor cell analysis.

Main Results:

• RSRC1 mutation identified as the cause of an autosomal recessive syndrome including intellectual disability, aberrant behavior, hypotonia, and mild facial dysmorphism.
• RSRC1 plays a role in alternative splicing and transcription regulation, impacting genes associated with intellectual disability, hypotonia, and schizophrenia.
• Patient-derived neural progenitor cells exhibit downregulated IGFBP3 expression, a gene implicated in behavioral and synaptic functions.

Conclusions:

• RSRC1 mutations lead to a distinct neurodevelopmental syndrome.
• RSRC1 is crucial for normal neurodevelopment, with its dysfunction contributing to intellectual disability and behavioral phenotypes.
• The findings suggest a novel genetic pathway involving RSRC1 and IGFBP3 in brain function and disease.