RGD Reference Report - Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation. - Rat Genome Database

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

Authors: Issa, L  Mueller, K  Seufert, K  Kraemer, N  Rosenkotter, H  Ninnemann, O  Buob, M  Kaindl, AM  Morris-Rosendahl, DJ 
Citation: Issa L, etal., Orphanet J Rare Dis. 2013 Apr 15;8:59. doi: 10.1186/1750-1172-8-59.
RGD ID: 11057920
Pubmed: PMID:23587236   (View Abstract at PubMed)
PMCID: PMC3639195   (View Article at PubMed Central)
DOI: DOI:10.1186/1750-1172-8-59   (Journal Full-text)

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 gamma-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary autosomal recessive microcephaly 3  IAGP 11057920DNA:nonsense mutation:exon: c.4441C>T (p.R1481X)(human)RGD 
primary autosomal recessive microcephaly 3  ISOCDK5RAP2 (Homo sapiens)11057920; 11057920DNA:nonsense mutation:exon: c.4441C>T (p.R1481X)(human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Agenesis of corpus callosum  IAGP 11057920DNA:nonsense mutation:exon: c.4441C>T (p.R1481X)(human)RGD 
Simplified gyral pattern  IAGP 11057920DNA:nonsense mutation:exon: c.4441C>T (p.R1481X)(human)RGD 
Sloping forehead  IAGP 11057920DNA:nonsense mutation:exon: c.4441C>T (p.R1481X)(human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cdk5rap2  (CDK5 regulatory subunit associated protein 2)

Genes (Mus musculus)
Cdk5rap2  (CDK5 regulatory subunit associated protein 2)

Genes (Homo sapiens)
CDK5RAP2  (CDK5 regulatory subunit associated protein 2)


Additional Information