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

Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann, Gudrun Nürnberg, Muhammad Farooq, Ilyas Ahmad, Thomas Alef, Hans Christian Hennies, Martin Technau, Janine Altmüller, Peter Frommolt, Holger Thiele, Angelika Anna Noegel*, Peter Nürnberg

*Corresponding author for this work
116 Citations (Scopus)


Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Issue number5
Pages (from-to)871-878
Number of pages8
Publication statusPublished - 04.05.2012

Research Areas and Centers

  • Research Area: Medical Genetics


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