CIT, a gene involved in neurogenic cytokinesis, is mutated in human primary microcephaly

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Medicine

Background:

• Autosomal recessive primary microcephaly (MCPH) is a static neurodevelopmental disorder defined by congenital microcephaly and intellectual disability.
• MCPH is genetically heterogeneous, with 16 genes (MCPH1-MCPH16) identified to date.
• Understanding the genetic basis of MCPH is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To identify the genetic cause of MCPH in a consanguineous family segregating the disorder.
• To investigate the role of the citron kinase (CIT) gene in neurodevelopmental processes.

Main Methods:

• Genome-wide homozygosity mapping to identify disease loci.
• Exome sequencing to detect causative variants in affected individuals.
• Sanger sequencing and cDNA analysis to confirm variant pathogenicity.

Main Results:

• A novel splice site variant (c.753+3A>T) in the CIT gene was identified in affected family members.
• This variant segregated with MCPH in the family and is predicted to disrupt normal CIT splicing.
• Loss of CIT expression leads to defects in neurogenic cytokinesis, impacting brain development.

Conclusions:

• The identified CIT splice site variant is the first reported cause of MCPH linked to this gene.
• Mutations in CIT disrupt neurogenic cytokinesis, contributing to the pathogenesis of primary microcephaly.
• This discovery expands the genetic landscape of MCPH and highlights CIT's role in brain development.