A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder causing intellectual disability and reduced head size.
• MCPH is genetically heterogeneous, with known causative genes often encoding centrosomal proteins.

Purpose of the Study:

• To identify the genetic cause of MCPH in a Pakistani family with two affected children.
• To investigate the role of centrosomal proteins in MCPH pathogenesis.

Main Methods:

• Homozygosity mapping was used to identify linkage regions in affected individuals.
• Candidate gene sequencing, including CEP135, was performed to identify mutations.
• Patient-derived fibroblasts were analyzed for cellular defects.

Main Results:

• A homozygous frameshift mutation in the CEP135 gene was identified in affected siblings.
• Patient fibroblasts exhibited multiple fragmented centrosomes and disorganized microtubules.
• These cellular defects were reproducible upon CEP135 knockdown or mutant overexpression.

Conclusions:

• The identified CEP135 mutation is the causal variant for MCPH in this family, establishing a new locus (MCPH8).
• This study reinforces the critical role of centrosomes and CEP135 in normal neurogenesis and brain development.