ORPHA: 2512; DO: 0070286;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q33.2 | Microcephaly 3, primary, autosomal recessive | 604804 | Autosomal recessive | 3 | CDK5RAP2 | 608201 |
A number sign (#) is used with this entry because primary microcephaly-3 (MCPH3) is caused by homozygous or compound heterozygous mutation in the CDK5RAP2 gene (608201) on chromosome 9q33.
For a phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Pagnamenta et al. (2012) reported a 6-year-old girl, born of consanguineous Somali parents, with primary microcephaly. She had delayed psychomotor development, microcephaly (-8.9 SD), and mild muscular hypotonia. The patient 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.
Lancaster et al. (2013) reported a patient with poor growth apparent during fetal life and postnatally who had severe microcephaly (-13.2 SD). The patient had short stature (-6.7 SD), prominent eyes, conical-shaped and widely spaced teeth, and mixed conductive sensorineural hearing loss. Developmental milestones were mildly/moderately delayed. Neuroimaging showed a simplified gyral pattern, small frontal lobes, and partial absence of the corpus callosum.
Tan et al. (2014) reported a 6-year-old girl of northern European/Caucasian and Cherokee ancestry with severe progressive microcephaly (-8.9 SD) and developmental delay. She did not have dysmorphic features, and brain MRI showed no structural abnormalities. The girl was 1 of triplets; the other 2 sisters were unaffected.
Pagnamenta et al. (2016) reported an 11-year-old boy, born of unrelated Caucasian parents, with MCPH3. In addition to progressive microcephaly (-5.5 SD), moderate learning difficulties, and significant speech delay, he had behavioral problems, including aggression, temper tantrums, overactivity, poor concentration, and poor socialization. He had a sloping forehead and prominent nose, as well as 11 cafe-au-lait spots. Brain imaging showed no migrational or callosal abnormalities.
The transmission pattern of MCPH3 in the family reported by Pagnamenta et al. (2012) was consistent with autosomal recessive inheritance.
By autozygosity mapping, Moynihan et al. (2000) identified a novel MCPH locus, MCPH3, at chromosome 9q34 in a large, multiaffected consanguineous pedigree. A maximum 2-point lod score of 3.76 (recombination fraction of 0.0) was observed for marker D9S290.
Lancaster et al. (2013) developed a human pluripotent stem cell-derived 3-dimensional organoid culture system, termed cerebral organoids, and demonstrated cerebral organoids derived from induced pluripotent stem cells generated from skin fibroblasts of a patient with compound heterozygous truncating mutations in the CDK5RAP2 gene.
In affected members of each of 2 families with MCPH3, one of which was previously described by Moynihan et al. (2000), Bond et al. (2005) identified a homozygous mutation in the CDK5RAP2 gene (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 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.
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.
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.
Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005. [PubMed: 15793586] [Full Text: https://doi.org/10.1038/ng1539]
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. Cerebral organoids model human brain development and microcephaly. Nature 501: 373-379, 2013. [PubMed: 23995685] [Full Text: https://doi.org/10.1038/nature12517]
Lizarraga, S. B., Margossian, S. P., Harris, M. H., Campagna, D. R., Han, A.-P., Blevins, S., Mudbhary, R., Barker, J. E., Walsh, C. A., Fleming, M. D. Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors. Development 137: 1907-1917, 2010. [PubMed: 20460369] [Full Text: https://doi.org/10.1242/dev.040410]
Moynihan, L., Jackson, A. P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R. F., Lench, N. J., Woods, C. G. A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Am. J. Hum. Genet. 66: 724-727, 2000. [PubMed: 10677332] [Full Text: https://doi.org/10.1086/302777]
Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U. Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities. Clin. Case Rep. 4: 952-956, 2016. [PubMed: 27761245] [Full Text: https://doi.org/10.1002/ccr3.663]
Pagnamenta, A. T., Murray, J. E., Yoon, G., Sadighi Akha, E., Harrison, V., Bicknell, L. S., Ajilogba, K., Stewart, H., Kini, U., Taylor, J. C., Keays, D. A., Jackson, A. P., Knight, S. J. L. A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss. Am. J. Med. Genet. 158A: 2577-2582, 2012. [PubMed: 22887808] [Full Text: https://doi.org/10.1002/ajmg.a.35558]
Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S. The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing. Brain Dev. 36: 351-355, 2014. [PubMed: 23726037] [Full Text: https://doi.org/10.1016/j.braindev.2013.05.001]