American journal of human genetics, 2012-05, Vol.90 (5), p.871-878
2012
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- Autor(en) / Beteiligte
- Titel
- A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function
- Ist Teil von
- American journal of human genetics, 2012-05, Vol.90 (5), p.871-878
- Ort / Verlag
- Cambridge, MA: Elsevier Inc
- Erscheinungsjahr
- 2012
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0002-9297eISSN: 1537-6605DOI: 10.1016/j.ajhg.2012.03.016Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3376485
- Format
- –
- Schlagworte
- Biological and medical sciences, Brain, Brain architecture, Carrier Proteins - genetics, Carrier Proteins - metabolism, Centrosome, Centrosomes, Child, Children, chromosome 2, chromosome 4, Chromosomes, Chromosomes, Human, Pair 4 - genetics, Chromosomes, Human, Pair 4 - metabolism, Congenital diseases, Exome, Exons, Female, Fibroblasts, Frameshift mutation, Fundamental and applied biological sciences. Psychology, Gene Knockdown Techniques, Gene mapping, General aspects. Genetic counseling, Genes, Genetic Linkage, Genetic Loci, Genetics of eukaryotes. Biological and molecular evolution, Growth rate, Head, Homozygote, Humans, Intellectual Disability - genetics, Intellectual Disability - physiopathology, Male, Malformations of the nervous system, Medical genetics, Medical sciences, Mental retardation, Microcephaly - genetics, Microcephaly - physiopathology, Microencephaly, Microtubules, Molecular and cellular biology, Mutation, Neurogenesis, Neurological disorders, Neurology, Organelles, Pakistan - epidemiology, Pedigree, Polymorphism, Single Nucleotide, Proteins, RNA Interference, RNA-mediated interference, Sequence Analysis, DNA