Kinetochore KMN network gene CASC5 mutated in primary microcephaly

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Cell Biology

Background:

• Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder causing significant brain size reduction.
• Several genes involved in centrosome and spindle pole functions are linked to MCPH.
• The genetic basis for some MCPH cases remains unknown.

Purpose of the Study:

• To identify novel genetic causes of autosomal recessive primary microcephaly (MCPH).
• To investigate the role of the CASC5 gene in human brain development and its potential link to MCPH.

Main Methods:

• Genetic analysis of patients from three consanguineous families with MCPH.
• Identification and characterization of a novel homozygous mutation in the CASC5 gene.
• Analysis of CASC5 protein function, localization, and interactions during mitosis.

Main Results:

• A rare homozygous mutation in CASC5 (encoding Blinkin/KNL1) was identified in MCPH patients.
• The mutation leads to a frameshift and truncation of the CASC5 protein, affecting kinetochore function.
• CASC5 is upregulated in the human fetal ventricular zone and is crucial for microtubule attachment and spindle-assembly checkpoint activation.

Conclusions:

• CASC5 is a novel gene associated with autosomal recessive primary microcephaly (MCPH).
• The study underscores the critical role of kinetochore integrity, specifically CASC5 function, in regulating human brain volumetric development.
• Accelerated evolution of CASC5 in the human lineage suggests its importance in primate brain evolution.