Abstract
BackgroundPrimary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist.Methods/ResultsWe sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent.ConclusionThese results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.
Highlights
Primary autosomal recessive microcephaly (MCPH) delineates a genetically heterogeneous and rare subgroup of congenital microcephalies characterized by a pronounced reduction of brain volume, of the neocortex, simplified gyral pattern and intellectual disability [1,2].Homozygous mutations of the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene, CDK5RAP2 (OMIM*608201), were identified in 2005 as a cause for MCPH type 3 (MCPH3, OMIM#604804) [3]
These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3
Despite considerable interest in MCPH as a neural stem cell defect and window into the control of neurogenesis in humans, the underlying pathomechanisms have not been definitively established and for MCPH3, no detailed radiological descriptions of patients or functional analyses in patient samples have been reported to date
Summary
Homozygous mutations of the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene, CDK5RAP2 (OMIM*608201), were identified in 2005 as a cause for MCPH type 3 (MCPH3, OMIM#604804) [3]. Despite considerable interest in MCPH as a neural stem cell defect and window into the control of neurogenesis in humans, the underlying pathomechanisms have not been definitively established and for MCPH3, no detailed radiological descriptions of patients or functional analyses in patient samples have been reported to date. Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. For MCPH3, no detailed radiological or histological descriptions exist
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