DO: 0112231;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q36.1 | ?Lissencephaly 7 with cerebellar hypoplasia | 616342 | Autosomal recessive | 3 | CDK5 | 123831 |
A number sign (#) is used with this entry because of evidence that lissencephaly-7 with cerebellar hypoplasia (LIS7) is caused by homozygous mutation in the CDK5 gene (123831) on chromosome 7q36. One such family has been reported.
Lissencephaly-7 with cerebellar hypoplasia (LIS7) is a severe neurodevelopmental disorder characterized by lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy (Magen et al., 2015).
For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Magen et al. (2015) reported a large, highly consanguineous kindred of Israeli Muslim descent in which 10 infants had a lethal form of lissencephaly. Patients presented at birth with abnormal features, including small head size, short forehead, low hairline, full cheeks, downslanting corners of the mouth, micrognathia, hirsutism, lymphedema, arthrogryposis multiplex, and clenched hands. Affected newborns had shallow breathing, head lag, absent reflexes, reduced responses to pain, and intractable seizures associated with burst-suppression pattern on EEG. All died from respiratory failure between 2 days and 3 months of age. Brain imaging showed extreme lissencephaly with complete agyria, cerebellar hypoplasia, and agenesis of the corpus callosum. Skeletal muscle biopsies of 2 patients showed nonspecific myopathic changes, such as small round skeletal muscle fibers with centralized nuclei. Neuropathologic examination of 1 patient showed smooth brain surface and severely disordered cortical lamination.
The transmission pattern of LIS7 in the family reported by Magen et al. (2015) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis in a consanguineous family segregating lethal lissencephaly, Magen et al. (2015) found linkage to a 6-Mb region on chromosome 7q35-q36.1 (maximum 2-point lod score of 4.87 at marker D7S636).
In 4 affected members of a highly consanguineous Israeli Muslim family with lethal autosomal recessive lissencephaly-7 with cerebellar hypoplasia, Magen et al. (2015) identified a homozygous splice site mutation in the CDK5 gene (123831.0001), resulting in premature termination. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Patient cells showed decreased amounts of mutant mRNA, consistent with nonsense-mediated mRNA decay, as well as undetectable levels of CDK5 protein, suggesting a complete loss of function. Complementation studies in yeast showed that the mutant protein was unable to rescue the growth defect of yeast with absence of the homologous Pho85 gene.
Cdk5, which is essential for the proper development of the central nervous system (CNS), is also implicated in numerous complex functions of the adult CNS, such as synaptic transmission, synaptic plasticity, and neuronal signaling. Hirasawa et al. (2004) found that conditional knockdown of the Cdk5 gene in neurons of perinatal mice resulted in neuronal migration defects.
Hirasawa, M., Ohshima, T., Takahashi, S., Longenecker, G., Honjo, Y., Veeranna, Pant, H. C., Mikoshiba, K., Brady, R. O., Kulkarni, A. B. Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects. Proc. Nat. Acad. Sci. 101: 6249-6254, 2004. [PubMed: 15067135] [Full Text: https://doi.org/10.1073/pnas.0307322101]
Magen, D., Ofir, A., Berger, L., Goldsher, D., Eran, A., Katib, N., Nijem, Y., Vlodavsky, E., Tzur, S., Behar, D. M., Fellig, Y., Mandel, H. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5. Hum. Genet. 134: 305-314, 2015. Note: Erratum: Hum. Genet. 134: 315 only, 2015. [PubMed: 25560765] [Full Text: https://doi.org/10.1007/s00439-014-1522-5]