Alternative titles; symbols
HGNC Approved Gene Symbol: CDK5RAP2
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38) : 9:120,388,875-120,580,167 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.2 | Microcephaly 3, primary, autosomal recessive | 604804 | Autosomal recessive | 3 |
The CDK5RAP2 gene encodes a centrosomal protein that localizes to the spindle poles during mitosis (summary by Hassan et al., 2007 and Lizarraga et al., 2010).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned CDK5RAP2, which they designated KIAA1633. The deduced protein contains 1,561 amino acids. RT-PCR ELISA detected moderate to high expression of CDK5RAP2 in all tissues and specific brain regions examined. Highest levels were detected in skeletal muscle, fetal liver, brain, kidney, and ovary. Within specific brain regions, highest expression was detected in thalamus, corpus callosum, substantia nigra, hippocampus, and caudate nucleus.
Using NCK5A (CDK5R1; 603460) as bait in a yeast 2-hybrid screen of a brain cDNA library, Ching et al. (2000) obtained a partial clone of CDK5RAP2, which they designated C48. Northern blot analysis detected expression in all tissues examined, with highest levels in heart and skeletal muscle. Ching et al. (2000) also cloned full-length rat Cdk5rap2 from a brain cDNA library. The deduced 217-amino acid rat protein has a serine-rich N terminus and shares a region of homology with restin (179838), an intermediate filament-associated protein.
Evans et al. (2006) stated that the CDK5RAP2 protein contains 2 structural maintenance of chromosomes (SMC; see 608685) domains.
Graser et al. (2007) reported that CEP215 encodes 2 isoforms containing 1,893 and 1,814 amino acids. Both isoforms have an N-terminal microtubule-association domain and 10 coiled-coil domains. Compared with the long isoform, the short isoform has a deletion near the C terminus that involves part of coiled-coil domain-9. Immunohistochemical and immunoelectron microscopic analyses of U2OS cells showed CEP215 at centriolar cylinders. CEP215 staining persisted on centrosomes throughout the cell cycle. Western blot analysis of HeLa, U2OS, and 293T cells detected CEP215 at an apparent molecular mass of approximately 210 kD.
Bond et al. (2005) stated that the CDK5RAP2 gene contains 34 exons. Evans et al. (2006) determined that the CDK5RAP2 gene contains 38 exons and spans 190 kb.
Graser et al. (2007) stated that the CDK5RAP2 gene maps to chromosome 9q33.2.
Ching et al. (2000) determined that rat Cdk5rap2 was phosphorylated by Cdk5 kinase (123831).
Using a small interfering RNA screen, Graser et al. (2007) found that depletion of CNAP1 (CEP2; 609689), rootletin (CROCC; 615776), pericentrin (PCNT; 605925), CEP68 (616889), or CEP215 reduced centrosome cohesion and caused centrosome splitting in U2OS, A549, and RPE1 cells. Depletion of CNAP1 and rootletin produced the most severe phenotype. Depletion of pericentrin caused loss of CEP215 from centrioles, but depletion of CEP215 had no effect on pericentrin. Graser et al. (2007) concluded that CEP215 and pericentrin functionally interact and influence centrosome cohesion through an indirect mechanism independent of CNAP1, rootletin, and CEP68.
Lancaster et al. (2013) developed a human pluripotent stem cell-derived 3-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These included a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulated features of human cortical development, namely, characteristic progenitor zone organization with abundant outer radial glial stem cells. Lancaster et al. (2013) used RNA interference and patient-specific induced pluripotent stem cells to model microcephaly caused by deficiency of CDK5RAP2 (MCPH3; 604804), a disorder that has been difficult to recapitulate in mice. Lancaster et al. (2013) demonstrated premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype.
Using a proximity interaction assay with U2OS cells, Firat-Karalar et al. (2014) found that full-length CEP152 (613529) interacted with CDK5RAP2. Coimmunoprecipitation analysis in HEK293T cells confirmed direct interaction between CEP152 and CDK5RAP2. Depletion of CEP152 reduced centrosome localization of CDK5RAP2.
In a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Moynihan et al. (2000) mapped the disorder to chromosome 9q34 by autozygosity mapping. Bond et al. (2005) used a positional cloning strategy to identify genes in this region in 2 families, including the one previously described by Moynihan et al. (2000). Genotyping polymorphic microsatellite markers in the 2 families narrowed the region to 2.2 Mb. Bioinformatic analysis of the region identified CDK5RAP2 as a likely candidate. A homozygous mutation in the CDK5RAP2 gene was identified in affected members of each of the 2 families (608201.0001-608201.0002, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat.
In a 6-year-old girl, born of consanguineous Somali parents, with MCPH3, Pagnamenta et al. (2012) identified a homozygous truncating mutation in the CDK5RAP2 gene (E234X; 608201.0003).
In a patient with MCPH3 and a simplified gyral pattern on brain imaging, Lancaster et al. (2013) identified compound heterozygous truncating mutations in the CDK5RAP2 gene (608201.0004 and 608201.0005).
In a 6-year-old girl of Caucasian and Cherokee ancestry with MCPH3 and normal brain imaging, Tan et al. (2014) identified compound heterozygous mutations in the CDK5RAP2 gene (608201.0006 and 608201.0007). The mutations were found by next-generation sequencing of targeted microcephaly genes. The girl was 1 of triplets; the other 2 sisters were unaffected.
In an 11-year-old boy with MCPH3, Pagnamenta et al. (2016) identified compound heterozygous mutations in the CDK5RAP2 gene (608201.0008 and 608201.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Associations Pending Confirmation
In 3 adult sibs, born of unrelated French Canadian parents, with isolated agenesis of the corpus callosum (see 217990), Jouan et al. (2016) identified compound heterozygous missense variants in the CDK5RAP2 gene (NM_018249.5): a c.280G-C transversion, resulting in a gly94-to-arg (G94R) substitution, and a c.3695A-G transition, resulting in an asn1232-to-ser (N1232S) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants affected highly conserved nucleotides. G94R was found in 2 of 288 unaffected controls, but neither homozygous nor compound heterozygous variants were found. Both variants were present at low frequencies in the ExAC database (G94R at 8.237 x 10(-6), N1232S at 8.238 x 10(-6)), but were not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases. Lymphoblastoid cells from 1 of the patients showed biallelic expression of the variants; functional studies of the variants were not performed. Jouan et al. (2016) suggested that hypomorphic CDK5RAP2 variants with residual function may predispose to agenesis of the corpus callosum, while more detrimental loss-of-function variants may result in the more severe phenotype of microcephaly.
The mouse Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy, and a predisposition to hematopoietic tumors. Lizarraga et al. (2010) found that the 'an' mutation was a homozygous mutation in the Cdk5rap2 gene that causes a deletion of exon 4. In addition to the hematopoietic phenotype, the mutant mice showed microcephaly with hypoplasia of several brain regions, including the cortex and hippocampus. Neuronal progenitors from the mutant mice showed proliferative and survival defects: they exited the cell cycle prematurely and many underwent apoptosis. These defects were associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. These findings suggested that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during the proliferation of neuronal progenitors.
In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804) previously described by Moynihan et al. (2000), Bond et al. (2005) identified a homozygous 243T-A transversion in exon 4 of the CDK5RAP2 gene, resulting in a ser81-to-ter (S81X) substitution.
In 4 sibs, born of consanguineous Pakistani parents of Kashmiri origin, with MCPH3, Hassan et al. (2007) identified a homozygous c.246T-A transversion in the CDK5RAP2 gene, resulting in a tyr82-to-ter (Y82X) substitution. The patients had a head circumference of -4 to -7 SD and mental retardation. The mutation was found by homozygosity mapping and candidate gene analysis, segregated with the disorder in the family, and was not present in 200 control chromosomes. Hassan et al. (2007) stated that this was the same mutation as that reported by Bond et al. (2005), and postulated a founder effect.
In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Bond et al. (2005) identified a homozygous A-to-G transition at position -15 of intron 26 of the CDK5RAP2 gene, resulting in a new splice acceptor site with the addition of 4 new amino acids and a premature stop codon.
In a 6-year-old girl, born of consanguineous Somali parents, with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Pagnamenta et al. (2012) identified a homozygous c.700G-T transversion in exon 8 of the CDK5RAP2 gene, resulting in a glu234-to-ter (E234X) substitution. The mutation was not found in over 5,000 Caucasian and African American samples in the Exome Variant Server database. The patient had delayed psychomotor development, microcephaly (-8.9 SD), and mild muscular hypotonia. She was diagnosed at age 3 years 10 months with moderate to severe sensorineural hearing loss, which may have been due to another genetic defect given the consanguinity in the family.
In a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Lancaster et al. (2013) identified compound heterozygous mutations in the CDK5RAP2 gene: a c.4546G-T transversion resulting in a glu1516-to-ter (E1516X) substitution, and a c.4672C-T transition resulting in an arg1558-to-ter (R1558X; 608201.0005) substitution. Each unaffected parent was heterozygous for 1 of the mutations. CDK5RAP2 protein was undetectable in patient cell lysates. The patient had severe microcephaly (-13.2 SD), short stature (-6.7 SD), simplified gyral pattern on brain imaging, delayed psychomotor development, and mixed conductive/sensorineural hearing loss.
For discussion of the arg1558-to-ter (R1558X) mutation in the CDK5RAP2 gene that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Lancaster et al. (2013), see 608201.0004.
In a 6-year-old girl with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Tan et al. (2014) identified compound heterozygous mutations in the CDK5RAP2 gene: a 5-bp deletion (c.524_528del) in exon 7, resulting in a frameshift and premature termination (Gln175ArgfsTer42), and a G-to-A transition in intron 26 (c.4005-1G-A; 608201.0007), predicted to result in a splicing defect. Each unaffected parent was heterozygous for 1 of the mutations, which were found by next-generation sequencing of targeted microcephaly genes and confirmed by Sanger sequencing. The mother of the patient was of northern European descent and the father was Caucasian with Cherokee ancestry. The girl was 1 of triplets; the other 2 sisters were unaffected. The patient had severe microcephaly (-8.9 SD) and developmental delay, but brain MRI showed no structural abnormalities.
For discussion of the splice site mutation in the CDK5RAP2 gene (c.4005-1G-A) that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Tan et al. (2014), see 608201.0006.
In an 11-year-old boy (patient BRC081), born of unrelated Caucasian parents, with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Pagnamenta et al. (2016) identified compound heterozygous mutations in the CDK5RAP2 gene: a G-to-C transversion (c.4604+1G-C, NM_018249.5) in exon 30, predicted to alter a splice site, and a 1-bp deletion (c.3097delG; 608201.0009) in exon 23, predicted to result in a frameshift and premature termination (Val1033fsTer41). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the ExAC database. Analysis of patient cells showed that c.4604+1G-C mutation resulted in alternative use of a cryptic exonic splice donor site, which would result in premature termination (Val1526fsTer15).
For discussion of the 1-bp deletion (c.3097delG, NM_018249.5) in the CDK5RAP2 gene, predicted to result in a frameshift and premature termination (Val1033fsTer41), that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Pagnamenta et al. (2016), see 608201.0008.
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