Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a significantly reduced brain size.
• Affected individuals exhibit a small, architecturally normal cerebral cortex and varying degrees of intellectual disability.
• MCPH is genetically heterogeneous, with mutations in the ASPM gene at the MCPH5 locus being a frequent cause, especially in certain populations.

Purpose of the Study:

• To investigate the role of the ASPM gene in primary microcephaly.
• To identify mutations in the ASPM gene in Pakistani and Kashmiri families affected with MCPH.
• To correlate genotype with the clinical phenotype, specifically the severity of mental retardation.

Main Methods:

• Ascertainment of ten Pakistani and one Kashmiri family with primary microcephaly.
• Screening for ASPM gene mutations in seven consanguineous families linked to the MCPH5 locus.
• Sequence variant analysis and prediction of protein-truncating effects.

Main Results:

• Two known (8508delGA, W1326X) and four novel (Y1712X, I1717X, Y3353X, R3244X) ASPM sequence variants were identified.
• All detected variants were predicted to result in protein truncation.
• The severity of mental retardation (mild to moderate) did not correlate with the specific mutation location within the ASPM gene.

Conclusions:

• Mutations in the ASPM gene are a significant cause of primary microcephaly in the studied Pakistani and Kashmiri populations.
• The identified ASPM variants lead to protein truncation, consistent with MCPH pathogenesis.
• Clinical severity of mental retardation in MCPH patients is not determined by the specific mutation site in the ASPM gene.