Protein-truncating mutations in ASPM cause variable reduction in brain size

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• Autosomal recessive primary microcephaly (MCPH) is a severe congenital condition characterized by reduced brain size and intellectual disability.
• Mutations in the ASPM gene are strongly implicated as a leading genetic cause of MCPH, particularly at the MCPH5 locus.
• Understanding ASPM gene mutations is crucial for diagnosing and potentially treating this neurodevelopmental disorder.

Purpose of the Study:

• To conduct the first comprehensive mutation screen of the entire ASPM gene.
• To identify and characterize mutations responsible for MCPH in a cohort of consanguineous families.
• To investigate the relationship between mutation location and phenotypic variability in MCPH patients.

Main Methods:

• Comprehensive mutation screening of the 10.4-kb ASPM gene.
• Analysis of 23 consanguineous families with affected individuals.
• Genotyping and phenotypic assessment of 51 individuals with MCPH.

Main Results:

• Nineteen distinct mutations were identified within the ASPM gene.
• All identified mutations were predicted to result in protein truncation.
• Mutations were distributed throughout the ASPM gene.
• Phenotypic variation, including the severity of microcephaly and intellectual disability, was observed but did not correlate with mutation position.

Conclusions:

• ASPM gene mutations are a frequent cause of autosomal recessive primary microcephaly.
• The identified mutations are predominantly protein-truncating, affecting ASPM gene function.
• The degree of microcephaly and intellectual impairment in MCPH patients shows variability independent of the specific mutation site within the ASPM gene.