Alternative titles; symbols
HGNC Approved Gene Symbol: CADPS2
Cytogenetic location: 7q31.32 Genomic coordinates (GRCh38) : 7:122,318,411-122,886,460 (from NCBI)
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned CADPS2, which they designated KIAA1591. The deduced protein shares 75% identity with mouse Cadps (604667). RT-PCR ELISA detected highest expression in whole brain, with intermediate expression in heart, lung, liver, kidney, pancreas, ovary, spinal cord, fetal brain, and fetal liver, and little to no expression in skeletal muscle, testis, and spleen. Within the specific brain regions examined, highest expression was in cerebellum.
By screening a human pancreas cDNA library with mouse Cadps, Cisternas et al. (2003) cloned CADPS2. The deduced 1,254-amino acid protein contains an N-terminal coiled-coil domain, followed by a C2 domain, a PH domain, and a C-terminal coiled-coil domain. The C2 domain is expected to mediate calcium and phospholipid binding. CADPS2 shares 80% amino acid identity with CADPS and 90% identity with mouse Cadps2. Northern blot analysis detected a 5.0-kb transcript in all adult and fetal tissues examined. Within specific brain regions, highest expression was detected in cerebellum, with lower expression in cerebral cortex, occipital pole, and frontal and temporal lobes, and weak expression in medulla, spinal cord, and putamen. A faint 5.2-kb transcript was also present in medulla. Semiquantitative PCR detected CADPS2 in all tissues examined, with highest levels in kidney and pancreas.
Cisternas et al. (2003) determined that the CADPS2 gene contains 28 exons and spans about 561 kb. The 5-prime end of the CADPS2 gene contains a CpG island and has 2 promoter regions. Cisternas et al. (2003) noted that the mouse Cadps2 gene appears to have a different exonic structure.
Using FISH, Cisternas et al. (2003) mapped the CADPS2 gene to chromosome 7q31.3.
In blood of 3 patients with autism (209850), including a pair of monozygotic twins, Sadakata et al. (2007) identified an aberrant CADPS2 mRNA transcript lacking exon 3 that segregated with the disorder in both families. No mutations were found around the splice donor or acceptor sites or branchpoints of intron 2 in the genomic sequences of these patients. Exon 3 skipping was predicted to cause a deletion of 111 residues in the protein, deleting a dynactin (DCTN1; 601143)-binding domain. Functional expression studies in cultured cells showed that the exon 3-skipped CADPS2 protein had almost normal brain-derived neurotrophic factor (BDNF; 113505)-releasing activity but was not properly transported into the axons of neocortical and cerebellar neurons.
Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) identified a total of 212 regions containing putative selective sweeps. Mutations in several genes in regions of selective sweeps, including CADPS2, DYRK1A (600855), NRG3 (605533), and AUTS2 (607270), have been associated with disorders affecting cognitive capacities. Green et al. (2010) hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
Sadakata et al. (2007) observed autistic-like behavioral features in Cadps2-knockout mice. Compared to wildtype mice, Cadps2-null mice showed impaired retention of spatial memory in a water maze test, impaired social interaction, hyperactivity during dark, maternal neglect, decreased exploratory behavior, and increased anxiety in a novel environment. Defects in sleep/wake regulation and circadian rhythmicity were also observed in the knockout mice. Cellular studies of Cadps2-null mouse brain showed that Cadps2 is critical for BDNF secretion from neocortical and cerebellar neurons, for the differentiation of neocortical and hippocampal neurons, and for the survival of cerebellar Purkinje cells.
Cisternas, F. A., Vincent, J. B., Scherer, S. W., Ray, P. N. Cloning and characterization of human CADPS and CADPS2, new members of the Ca(2+)-dependent activator for secretion protein family. Genomics 81: 279-291, 2003. [PubMed: 12659812] [Full Text: https://doi.org/10.1016/s0888-7543(02)00040-x]
Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. A draft sequence of the Neandertal genome. Science 328: 710-722, 2010. [PubMed: 20448178] [Full Text: https://doi.org/10.1126/science.1188021]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Sadakata, T., Washida, M., Iwayama, Y., Shoji, S., Sato, Y., Ohkura, T., Katoh-Semba, R., Nakajima, M., Sekine, Y., Tanaka, M., Nakamura, K., Iwata, Y., Tsuchiya, K. J., Mori, N., Detera-Wadleigh, S. D., Ichikawa, H., Itohara, S., Yoshikawa, T., Furuichi, T. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J. Clin. Invest. 117: 931-943, 2007. [PubMed: 17380209] [Full Text: https://doi.org/10.1172/JCI29031]