Alternative titles; symbols
HGNC Approved Gene Symbol: DAB1
SNOMEDCT: 719301002;
Cytogenetic location: 1p32.2-p32.1 Genomic coordinates (GRCh38): 1:56,994,778-58,546,726 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.2-p32.1 | Spinocerebellar ataxia 37 | 615945 | Autosomal dominant | 3 |
The reelin (RELN; 600514) signaling pathway plays a critical role in the correct positioning of neurons within the developing brain. Animal studies have shown that DAB1 serves as an intracellular adaptor that is tyrosine phosphorylated when reelin binds to the lipoprotein receptors VLDLR (192977) and APOER2 (LRP8; 602600) on the surface of neurons (Huang et al., 2005).
By RT-PCR of human embryonic brain RNA using degenerate primers based on mouse Dab1, Lambert de Rouvroit and Goffinet (1998) cloned human DAB1. The deduced 555-amino acid protein contains a putative N-terminal phosphotyrosine-binding (PTB) domain. DAB1 shares 96% overall amino acid identity with the 555-amino acid mouse Dab1 isoform, and the 2 proteins are identical over their first 271 amino acids. DAB1 shares significant similarity with Drosophila 'disabled' (dab).
By 5-prime RACE of human and mouse embryonic brain RNA, Bar et al. (2003) identified 6 alternative 5-prime UTRs for human DAB1 and 4 alternative 5-prime UTRs for mouse Dab1. Three 5-prime UTRs, which the authors called UTRs 1A, 1B, and 1D, are conserved between mouse and human. UTR 1B, which contains 7 exons in human and 10 exons in mouse, contains several upstream ORFs and numerous upstream ATG codons preceding the major translation initiation site, and some of the ORFs are conserved between mouse and human. RT-PCR of mouse tissues detected transcripts containing UTR 1B only in brain, whereas transcripts containing UTRs 1A and 1D were detected in brain, testis, kidney, and liver, but not in spleen, heart, or thymus. PCR analysis of mouse brain at various developmental stages revealed weak UTR 1B expression at embryonic days 11 and 12, and stronger expression at embryonic day 15, at birth, and in adult.
Using RT-PCR, McAvoy et al. (2008) found that DAB1 was expressed in all normal human tissues examined, including brain, breast, cervix, endometrium, prostate, and ovary. It was also expressed in cell lines derived from normal ovarian surface epithelium and normal breast epithelium.
Seixas et al. (2017) noted that the expression of DAB1 is very complex because it contains several alternative first exons that can result in transcripts with variable 5-prime UTRs. Various transcripts were found in multiple human central nervous system regions, including the cerebellum, and all showed higher expression in human fetal brain tissue compared to adult brain.
Bar et al. (2003) determined that the DAB1 gene spans more than 1.2 Mb. Exons 2 through 14 span more than 294 kb and contain the coding region for the major DAB1 isoform. Exon 15 contains the 3-prime UTR. Multiple 5-prime exons are spread over a 961-kb region and produce 6 alternative 5-prime UTRs. The most complex 5-prime UTR, UTR 1B, is made up of 7 exons.
By analysis of radiation hybrids, Lambert de Rouvroit and Goffinet (1998) mapped the DAB1 gene to chromosome 1p32-p31. This region shows homology of synteny with the segment of mouse chromosome 4 containing Dab1.
Studies in mice have shown that layering of neurons in the cerebral cortex and cerebellum requires Reln and Dab1 (see ANIMAL MODEL). By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, Vldlr and Apoer2, are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1.
Using in vitro binding experiments, Hiesberger et al. (1999) showed that Reln bound directly and specifically to the extracellular domains of Vldlr and ApoER2. Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibited a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons.
Using immunolabeling, Dulabon et al. (2000) detected coexpression of Dab1 and alpha-3 (ITGA3; 605025)-beta-1 (ITGB1; 135630) integrin receptor in mouse embryonic cortical neurons with overlapping subcellular localization. They also observed reduced levels of Dab1 protein and elevated expression of a Reln fragment in cerebral cortices of alpha-3-beta-1 integrin-deficient mice. Dulabon et al. (2000) concluded that reelin/alpha-3-beta-1 integrin interactions regulate Dab1 protein levels but not Dab1 phosphorylation.
Huang et al. (2005) stated that the PTB domain of mouse Dab1 binds to APP (104760)-type transmembrane receptors and to lipoprotein receptors. The PTB domain also exhibits a pleckstrin (PLEK; 173570) homology (PH) domain-like function, whereby it binds to phosphoinositides (PI), with lys45 being critical for binding to phosphatidylinositol-4,5-bisphosphate. Huang et al. (2005) found that PI binding targeted Dab1 to the membrane, where it was subject to basal phosphorylation independent of reelin, Vldlr, and Apoer2. This receptor-independent membrane targeting of Dab1 was required for interaction of Dab1 with the downstream signaling proteins Src (190090) and Crk (164762), and disruption of PI binding prevented reelin-induced Dab1 hyperphosphorylation.
Honda and Nakajima (2006) found that mouse Dab1 shuttled between the cytoplasm and nucleus. Inhibition of the Ran (601179)-GTP-dependent nuclear export protein Crm1 (XPO1; 602559) in a mouse neuroblastoma cell line resulted in nuclear accumulation of Dab1. Mutagenesis analysis revealed that Dab1 contains 2 leucine-rich nuclear export signal sequences and a bipartite nuclear localization signal sequence. Honda and Nakajima (2006) also showed that Dab1 interacted directly with Crm1 in a Ran-GTP-dependent manner.
McAvoy et al. (2008) found that DAB1 mRNA and protein expression was reduced in a variety of human cancers, especially in brain and endometrial cancers. Experimental overexpression of DAB1 in a human breast cancer cell line inhibited cell growth.
Using overexpression and knockdown studies with cultured rat and mouse hippocampal and cortical neurons, Matsuki et al. (2010) found that a signaling pathway containing Stk25 (602255), Lkb1 (STK11; 602216), Strad (STRADA; 608626), and the Golgi protein Gm130 (GOLGA2; 602580) promoted Golgi condensation and multiple axon outgrowth while inhibiting Golgi deployment into dendrites and dendritic growth. This signaling pathway acted in opposition to the reelin-Dab1 pathway, which tended to inhibit Golgi condensation and axon outgrowth and favor Golgi deployment into dendrites and dendrite outgrowth.
Segarra et al. (2018) found that the neuronal guidance cue reelin (600514) possesses proangiogenic activities that ensure the communication of endothelial cells with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. APOE receptor 2 (602600) and Dab1 expressed in endothelial cells are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in endothelial cells leads to a reduced secretion of laminin-alpha 4 (LAMA4; 600133) and decreased activation of integrin-beta 1 (ITGB1; 135630) in glial cells, which in turn control neuronal migration and barrier properties of the neurovascular unit. Thus, Segarra et al. (2018) concluded that reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication.
In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; 615945), Seixas et al. (2017) identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality.
In affected members of 4 unrelated families with SCA37, all from the same region in southern Spain, Corral-Juan et al. (2018) identified an unstable intronic ATTTC(n) pentanucleotide repeat within a noncoding regulatory region of the DAB1 gene. The ATTTC repeat ranged from 46 to 71 repeats, and there was a significant inverse correlation between repeat size and age at onset in males, but not in females. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. Corral-Juan et al. (2018) suggested that the mutation resulted in a gain of function.
Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration and defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the product of the gene mutant in reeler, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in mouse Dab1, a homolog of Drosophila dab. Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene. Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain.
Howell et al. (1997) showed that targeted disruption of the mouse Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype.
By examining mice deficient in either Reln or Dab1, Rice et al. (2001) found that expression of both genes was essential for the patterning of synaptic connectivity in the retina. Physiologic studies of mice deficient in either gene detected attenuated rod-driven retinal responses that were associated with a decrease in rod bipolar cell density and an abnormal distribution of processes in the inner plexiform layer.
Sanada et al. (2004) found that individual neurons in the cortex of Dab1-deficient scrambler mice exhibited an abnormal mode and tempo of radial migration, which was associated with impaired detachment from radial glial cells. Glial detachment depended on alpha-3 integrin signaling that was regulated by the phosphorylation state of Dab1 residues tyr220 and tyr232. Sanada et al. (2004) concluded that a functional link between DAB1 phosphorylation and ITGA3 signaling drives the timely detachment of migrating neurons from radial glial fibers.
In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; 615945), Seixas et al. (2017) identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion was within a simple ATTTT/AAAAT repeat that localized to the polymorphic middle A-rich region of an AluJb sequence. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. The insertion was not detected in 520 control Portuguese chromosomes. The heterozygous ATTTC(n) insertion, ranging from 31 to 75 repeats, was always flanked by (ATTTT)n tracts larger than 58 repeats. In every disease allele, the insertion site was identical and placed in the middle of the normal ATTTT repeat, thus maintaining the pentanucleotide repeat structure. Sequence analysis of 260 control individuals showed that none contained the pathologic ATTTC repeat insertion. The distribution of normal ATTTT/AAAAT repeats in over 500 control subjects showed mostly alleles shorter than 30 repeats, with a rare group of larger alleles ranging from 30 to 400 repeats (about 7%). In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality.
Corral-Juan et al. (2018) identified an unstable ATTTC(n) pentanucleotide repeat in the DAB1 gene in affected members of 4 unrelated families from the south of Spain with SCA37, including the large family (AT-901) previously reported by Serrano-Munuera et al. (2013). Haplotype analysis suggested a founder effect. Corral-Juan et al. (2018) stated that the repeat occurred in intron 11. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. Corral-Juan et al. (2018) suggested that the mutation resulted in a gain of function.
Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., Goffinet, A. M. The gene encoding Disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse. J. Biol. Chem. 278: 5802-5812, 2003. [PubMed: 12446734] [Full Text: https://doi.org/10.1074/jbc.M207178200]
Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37. Brain 141: 1981-1997, 2018. [PubMed: 29939198] [Full Text: https://doi.org/10.1093/brain/awy137]
Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S. Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration. Neuron 27: 33-44, 2000. [PubMed: 10939329] [Full Text: https://doi.org/10.1016/s0896-6273(00)00007-6]
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24: 481-489, 1999. [PubMed: 10571241] [Full Text: https://doi.org/10.1016/s0896-6273(00)80861-2]
Honda, T., Nakajima, K. Mouse Disabled 1 (DAB1) is a nucleocytoplasmic shuttling protein. J. Biol. Chem. 281: 38951-38965, 2006. [PubMed: 17062576] [Full Text: https://doi.org/10.1074/jbc.M609061200]
Howell, B. W., Hawkes, R., Soriano, P., Cooper, J. A. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389: 733-737, 1997. [PubMed: 9338785] [Full Text: https://doi.org/10.1038/39607]
Huang, Y., Shah, V., Liu, T., Keshvara, L. Signaling through Disabled 1 requires phosphoinositide binding. Biochem. Biophys. Res. Commun. 331: 1460-1468, 2005. [PubMed: 15883038] [Full Text: https://doi.org/10.1016/j.bbrc.2005.04.064]
Lambert de Rouvroit, C., Goffinet, A. M. Cloning of human DAB1 and mapping to chromosome 1p31-p32. Genomics 53: 246-247, 1998. [PubMed: 9790777] [Full Text: https://doi.org/10.1006/geno.1998.5523]
Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M. R., Hardy, J. A., Olson, E. C., Howell, B. W. Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143: 826-836, 2010. [PubMed: 21111240] [Full Text: https://doi.org/10.1016/j.cell.2010.10.029]
McAvoy, S., Zhu, Y., Perez, D. S., James, C. D., Smith, D. I. Disabled-1 is a large common fragile site gene, inactivated in multiple cancers. Genes Chromosomes Cancer 47: 165-174, 2008. [PubMed: 18008369] [Full Text: https://doi.org/10.1002/gcc.20519]
Rice, D. S., Nusinowitz, S., Azimi, A. M., Martinez, A., Soriano, E., Curran, T. The reelin pathway modulates the structure and function of retinal synaptic circuitry. Neuron 31: 929-941, 2001. [PubMed: 11580894] [Full Text: https://doi.org/10.1016/s0896-6273(01)00436-6]
Sanada, K., Gupta, A., Tsai, L.-H. Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis. Neuron 42: 197-211, 2004. [PubMed: 15091337] [Full Text: https://doi.org/10.1016/s0896-6273(04)00222-3]
Segarra, M., Aburto, M. R., Cop, F., Llao-Cid, C., Hartl, R., Damm, M., Bethani, I., Parrilla, M., Husainie, D., Schanzer, A., Schlierbach, H., Acker, T., Mohr, L., Torres-Masjoan, L., Ritter, M., Acker-Palmer, A. Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system. Science 361: eaao2861, 2018. Note: Electronic Article. [PubMed: 30139844] [Full Text: https://doi.org/10.1126/science.aao2861]
Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others. A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia. Am. J. Hum. Genet. 101: 87-103, 2017. [PubMed: 28686858] [Full Text: https://doi.org/10.1016/j.ajhg.2017.06.007]
Serrano-Munuera, C., Corral-Juan, M., Stevanin, G., San Nicolas, H., Roig, C., Corral, J., Campos, B., de Jorge, L., Morcillo-Suarez, C., Navarro, A., Forlani, S., Durr, A., Kulisevsky, J., Brice, A., Sanchez, I., Volpini, V., Matilla-Duenas, A. New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32. JAMA Neurol. 70: 764-771, 2013. [PubMed: 23700170] [Full Text: https://doi.org/10.1001/jamaneurol.2013.2311]
Sheldon, M., Rice, D. S., D'Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B. W., Cooper, J. A., Goldwitz, D., Curran, T. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389: 730-733, 1997. [PubMed: 9338784] [Full Text: https://doi.org/10.1038/39601]
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97: 689-701, 1999. [PubMed: 10380922] [Full Text: https://doi.org/10.1016/s0092-8674(00)80782-5]
Ware, M. L., Fox, J. W., Gonzalez, J. L., Davis, N. M., Lambert de Rouvroit, C., Russo, C. J., Chua, S. C., Jr., Goffinet, A. M., Walsh, C. A. Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse. Neuron 19: 239-249, 1997. [PubMed: 9292716] [Full Text: https://doi.org/10.1016/s0896-6273(00)80936-8]