HGNC Approved Gene Symbol: TIAM1
Cytogenetic location: 21q22.11 Genomic coordinates (GRCh38): 21:31,118,418-31,559,087 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.11 | Neurodevelopmental disorder with language delay and seizures | 619908 | Autosomal recessive | 3 |
The TIAM1 gene encodes a guanine nucleotide exchange factor (GEF) that regulates RAC1 (602048) signaling pathways, which affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network (summary by Lu et al., 2022).
To identify genes involved in metastasis by insertional mutagenesis, Habets et al. (1994) infected mouse BW5147 T-lymphoma cells with Moloney murine leukemia virus, resulting in 5 to 20 proviral insertions per cell. By this 'proviral tagging' method, invasive variants were selected on monolayers of fibroblasts. Disrupting proviral insertions were found in these cells within the coding exons of a gene designated Tiam1 (T-cell lymphoma invasion and metastasis-1). Selected clones were also metastatic in nude mice, and transfection of a truncated Tiam1 cDNA into noninvasive cells transmitted the invasive phenotype. Northern blot analysis demonstrated highest expression in the brain and testis. The mouse cDNA was isolated from a brain library and shown to encode a 1,591-amino acid protein which is serine rich and has regions of similarity to the Dbl-homologous (DH) domain found in GDP-GTP exchangers. The protein sequence also contains a pleckstrin-homologous (PH) domain thought to be involved in protein-protein interactions. Habets et al. (1995) cloned the human TIAM1 cDNA from a brain library using the mouse cDNA as a probe. The human protein is 95% identical to the mouse homolog. The authors speculated that TIAM1 may function in cellular signaling by activation of a Rho-like GTPase that regulates the cytoskeletal organization.
Using cell culture and in vitro assays, Lambert et al. (2002) provided evidence that mammalian Tiam1 is a Rac (602048)-specific guanine nucleotide exchange factor that preferentially associates with activated GTP-bound Ras (190020) through a Ras-binding domain. Activated Ras and Tiam1 cooperated to produce Rac-GTP in a PI3K (see 601232)-dependent manner. Lambert et al. (2002) concluded that Tiam1 can directly mediate Ras activation of Rac.
Zhang and Macara (2006) demonstrated that Pard3 (606745) binds directly to TIAM1 and spatially restricts it to dendritic spines. Proper expression of both proteins was necessary for normal dendritic spine development in rat hippocampal neurons. Depletion of Pard3 using small hairpin RNAs resulted in the formation of abnormal filopodia- and lamellipodia-like dendritic protrusions instead of the normal mushroom-like head and neck structure. Thus, a balance of PARD3 and TIAM1 is essential for modulating Rac-GTP levels to allow proper spine morphogenesis.
Miyamoto et al. (2006) found that Bdnf (113505), acting through Trkb (NTRK2; 600456), directly bound and activated Tiam1 by phosphorylating tyr829, leading to Rac1 activation and lamellipodia formation in COS-7 cells and increased neurite outgrowth in rat cortical neurons. A tyr829-to-phe mutation in Tiam1 blocked these Bdnf-induced changes in cellular morphology.
EPHB receptor tyrosine kinases are involved in formation and remodeling of dendritic spines, which receive the majority of excitatory synaptic inputs in the brain. Using immunoprecipitation, Western blot, and immunocytochemical analyses Tolias et al. (2007) showed that the PH domain, coiled-coil domain, and an adjacent region of TIAM1 interacted with EPHB2 (600997). The interaction led to phosphorylation and recruitment of TIAM1 to EPHB complexes containing NMDA glutamate receptors. Mutation and RNA interference analyses revealed that disruption of TIAM1 function blocked EPHB2-induced spine formation. Tolias et al. (2007) proposed that EPHB receptors regulate spine development, in part, by recruiting and activating TIAM1, which leads to RAC1-dependent actin remodeling required for spine formation.
Habets et al. (1995) mapped the mouse Tiam1 gene to the distal end of chromosome 16, 3.8 cM centromeric of Ets2. They mapped the human homolog to the syntenic region 21q22 between the centromere and AML1 (151385). Chen and Antonarakis (1995) localized the TIAM1 gene to 21q22.1 between markers D21S298 and D21S404 by inclusion within a YAC contig..
In 5 patients from 4 unrelated families with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908), Lu et al. (2022) identified homozygous or compound heterozygous missense mutations in the TIAM1 gene (600687.0001-600687.0006). Mutations in the first family were identified through exome sequencing; subsequent families were identified through the GeneMatcher Program after exome sequencing detected TIAM1 mutations. The mutations segregated with the disorder in the families; the mutations were either absent from or present only in the heterozygous state at a low frequency in the gnomAD database. The mutations occurred throughout the gene. Detailed studies of 3 of the variants (R23C, L862F, and G328V) in Drosophila showed variable loss-of-function effects that may have been limited by toxicity, but the findings supported the hypothesis that the mutant alleles are partial loss-of-function variants with a dosage effect.
Malliri et al. (2002) generated mice lacking Tiam1 and demonstrated that Tiam1 -/- mice are resistant to the development of RAS-induced skin tumors initiated with 7,12-dimethylbenzanthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate. Moreover, the few tumors produced in Tiam1 -/- mice grew much slower than did tumors in wildtype mice. Tiam1-deficient primary embryonic fibroblasts were also resistant to Ras(V12)-induced focus formation. Analysis of Tiam1 heterozygotes indicated that both tumor initiation and promotion were dependent on the TIAM1 gene dose. Tiam1 deficiency was associated with increased apoptosis during initiation and with impeded proliferation during promotion. Although the number of tumors in Tiam1 -/- mice was small, a greater proportion progressed to malignancy, suggesting that Tiam1 deficiency promotes malignant conversion. Malliri et al. (2002) concluded that their studies identified RAC activator TIAM1 as a critical regulator of different aspects of Ras-induced tumor formation.
In Drosophila, Lu et al. (2022) found expression of the TIAM1 ortholog 'still life' (sif) within neurons in the central nervous system of both larvae and adult animals. It was not expressed in glial cells. Knockdown of sif in Drosophila resulted in variably decreased survival, climbing defects, and seizure-like behavior. Moreover, knockdown of the sif gene specifically in neurons mimicked the phenotype of ubiquitous knockdown, indicating that the defects were caused by neuronal loss of sif. Expression of wildtype TIAM1 partially rescued the survival rate, but not neurologic deficits, of mutant flies, although this was limited by toxicity of TIAM1 expression.
In a pair of 35-year-old monozygotic twin brothers (family 1) with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908), Lu et al. (2022) identified compound heterozygous missense mutations in the TIAM1 gene: a c.67C-T transition (c.67C-T, NM_001353694), resulting in an arg23-to-cys (R23C) substitution, and a c.2584C-T transition, resulting in a leu862-to-phe (L862F; 600687.0002) substitution. The mutations, which were found by exome sequencing, segregated with the disorder in the family. Both variants were present in the heterozygous state at a low frequency in the gnomAD database (4.04 x 10(-4) and 3.98 x 10(-6), respectively). Detailed studies in Drosophila indicated that the mutations resulted in a partial loss of function.
For discussion of the c.2584C-T transition (c.2584C-T, NM_001353694) in the TIAM1 gene, resulting in a leu862-to-phe (L862F) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908) by Lu et al. (2022), see 600687.0001.
In a 3-year-old boy, born of consanguineous parents (family 2), with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908), Lu et al. (2022) identified a homozygous c.983G-T transversion (c.983G-T, NM_001353694) in the TIAM1 gene, resulting in a gly328-to-val (G328V) substitution. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was present in the heterozygous state at a low frequency in the gnomAD database (8.18 x 10(-6)). Detailed studies in Drosophila indicated that the mutation resulted in a partial loss of function.
In a 7-year-old boy, born of consanguineous parents (family 3), with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908), Lu et al. (2022) identified a homozygous c.4640C-A transversion (c.4640C-A, NM_001353694) in the TIAM1 gene, resulting in an ala1547-to-glu (A1547E) substitution. The mutation, which was found by exome sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database.
In a 6-year-old girl (family 4) with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908) Lu et al. (2022) identified compound heterozygous missense mutations in the TIAM1 gene: a c.1144G-C transversion (c.1144G-C, NM_001353694), resulting in a gly382-to-arg (G382R) substitution, and a c.4016C-T transition, resulting in an ala1339-to-val (A1339V; 600687.0006) substitution. Both variants were present in the heterozygous state at a low frequency in the gnomAD database (5.66 x 10(-5) and 3.98 x 10(-6), respectively).
For discussion of the c.4016C-T transition (c.4016C-T, NM_001353694) in the TIAM1 gene, resulting in an ala1339-to-val (A1339V) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with language delay and seizures (NEDLDS; 619908) by Lu et al. (2022), see 600687.0005.
Chen, H., Antonarakis, S. E. Localization of a human homolog of the mouse Tiam-1 gene to chromosome 21q22.1. Genomics 30: 123-127, 1995. [PubMed: 8595894] [Full Text: https://doi.org/10.1006/geno.1995.0025]
Habets, G. G. M., Scholtes, E. H. M., Zuydgeest, D., van der Kammen, R. A., Stam, J. C., Berns, A., Collard, J. G. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77: 537-549, 1994. [PubMed: 7999144] [Full Text: https://doi.org/10.1016/0092-8674(94)90216-x]
Habets, G. G. M., van der Kammen, R. A., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Hagemeijer, A., Collard, J. G. The invasion-inducing TIAM1 gene maps to human chromosome band 21q22 and mouse chromosome 16. Cytogenet. Cell. Genet. 70: 48-51, 1995. [PubMed: 7736788] [Full Text: https://doi.org/10.1159/000133989]
Habets, G. G. M., van der Kammen, R. A., Stam, J. C., Michiels, F., Collard, J. G. Sequence of the human invasion-inducing TIAM1 gene, its conservation in evolution and its expression in tumor cell lines of different tissue origin. Oncogene 10: 1371-1376, 1995. [PubMed: 7731688]
Lambert, J. M., Lambert, Q. T., Reuther, G. W., Malliri, A., Siderovski, D. P., Sondek, J., Collard, J. G., Der, C. J. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol. 4: 621-625, 2002. [PubMed: 12134164] [Full Text: https://doi.org/10.1038/ncb833]
Lu, S., Hernan, R., Marcogliese, P. C., Huang, Y., Gertler, T. S., Akcaboy, M., Liu, S., Chung, H., Pan, X., Sun, X., Oguz, M. M., Oztoprak, U., de Baaij, J. H. F., Ivanisevic, J., McGinnis, E., Guillen Sacoto, M. J., Chung, W. K., Bellen, H. J. Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures. Am. J. Hum. Genet. 109: 571-586, 2022. [PubMed: 35240055] [Full Text: https://doi.org/10.1016/j.ajhg.2022.01.020]
Malliri, A., van der Kammen, R. A., Clark, K., van der Valk, M., Michiels, F., Collard, J. G. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417: 867-871, 2002. [PubMed: 12075356] [Full Text: https://doi.org/10.1038/nature00848]
Miyamoto, Y., Yamauchi, J., Tanoue, A., Wu, C., Mobley, W. C. TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc. Nat. Acad. Sci. 103: 10444-10449, 2006. [PubMed: 16801538] [Full Text: https://doi.org/10.1073/pnas.0603914103]
Tolias, K. F., Bikoff, J. B., Kane, C. G., Tolias, C. S., Hu, L., Greenberg, M. E. The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc. Nat. Acad. Sci. 104: 7265-7270, 2007. [PubMed: 17440041] [Full Text: https://doi.org/10.1073/pnas.0702044104]
Zhang, H., Macara, I. G. The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis. Nature Cell Biol. 8: 227-237, 2006. [PubMed: 16474385] [Full Text: https://doi.org/10.1038/ncb1368]