Unknown

Dataset Information

0

Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.

ABSTRACT: BACKGROUND: Primary 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/RESULTS: We 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 ?-tubulin localization to the centrosome were apparent. CONCLUSION: These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.

SUBMITTER: Issa L 

PROVIDER: S-EPMC3639195 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.

Issa Lina L   Mueller Katrin K   Seufert Katja K   Kraemer Nadine N   Rosenkotter Henning H   Ninnemann Olaf O   Buob Michael M   Kaindl Angela M AM   Morris-Rosendahl Deborah J DJ  

Orphanet journal of rare diseases 20130415

<h4>Background</h4>Primary 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 u  ...[more]

Similar Datasets

Unknown Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum.
| S-EPMC3123551 | biostudies-literature
Unknown Molecular and cellular basis of autosomal recessive primary microcephaly.
| S-EPMC4274849 | biostudies-literature
Unknown Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.
| S-EPMC2072945 | biostudies-literature
Unknown A novel splice-site mutation in the ASPM gene underlies autosomal recessive primary microcephaly.
| S-EPMC6074201 | biostudies-literature
Unknown A novel non sense mutation in WDR62 causes autosomal recessive primary microcephaly: a case report.
| S-EPMC6052603 | biostudies-literature
Unknown A Novel Deletion Mutation in ASPM Gene in an Iranian Family with Autosomal Recessive Primary Microcephaly.
| S-EPMC3943041 | biostudies-literature
Unknown Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter.
| S-EPMC1377307 | biostudies-other
Unknown Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings.
| S-EPMC1199363 | biostudies-literature
Unknown A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.
| S-EPMC1288125 | biostudies-literature
Unknown Autosomal Recessive Primary Microcephaly: Not Just a Small Brain
| S-EPMC8802810 | biostudies-literature