Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Primary microcephaly (MCPH) is a congenital disorder causing reduced brain size and intellectual disability.
• MCPH is genetically diverse, with six previously identified loci (MCPH1-MCPH6).
• The genetic basis for a significant portion of MCPH cases remains unknown.

Purpose of the Study:

• To identify novel genetic loci responsible for primary microcephaly.
• To investigate the genetic heterogeneity of MCPH.
• To understand the role of specific genes in human brain development.

Main Methods:

• Genome-wide linkage analysis was performed on families with MCPH.
• Genetic mapping was used to identify the chromosomal location of a new MCPH locus.
• Mutation screening of candidate genes, including STIL, was conducted in affected individuals.

Main Results:

• A novel locus, MCPH7, was mapped to chromosome 1p32.3-p33.
• Five families showed linkage to the MCPH7 locus, with a maximum multipoint LOD score of 6.97.
• Three distinct homozygous mutations in the STIL gene were identified in patients linked to MCPH7, all predicted to cause protein truncation.

Conclusions:

• The STIL gene is a new causative gene for primary microcephaly.
• The centrosome and its associated proteins play a critical role in human neurogenesis.
• Identification of MCPH7 expands the genetic landscape of primary microcephaly and aids in diagnosis.