Alternative titles; symbols
HGNC Approved Gene Symbol: MAD1L1
Cytogenetic location: 7p22.3 Genomic coordinates (GRCh38) : 7:1,815,795-2,232,945 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.3 | Lymphoma, B-cell, somatic | 3 | ||
| Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition | 620189 | Autosomal recessive | 3 | |
| Prostate cancer, somatic | 176807 | 3 |
The MAD1L1 gene encodes an essential component of the mitotic spindle assembly checkpoint (SAC). It recruits the mitotic checkpoint complex (MCC) component MAD2L1 (601467) to unattached kinetochores to ensure accurate chromosome segregation during cell division (summary by Villarroya-Beltri et al., 2022).
In a search for cellular targets of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax, Jin et al. (1998) identified TXBP181 (Tax binding protein-181), which they characterized as the human homolog of yeast mitotic checkpoint MAD1 (mitotic arrest-deficient-1) protein. Evidence supporting TXBP181 (MAD1L1) as the human homolog of yeast MAD1 included strong sequence conservation with yeast MAD1, hyperphosphorylation during S/G2/M phases and upon treatment of cells with nocodazole, and binding to human MAD2L1 (601467). MAD1L1 functions as a homodimer. It localizes to the centrosome during metaphase and to the spindle midzone and the midbody during anaphase and telophase. Expression of either Tax or a transdominant-negative MAD1L1 results in multinucleated cells, a phenotype consistent with a loss of MAD1L1 function. Jin et al. (1998) proposed a model of viral transformation in which Tax targets MAD1L1, thereby abrogating a mitotic checkpoint.
Gene-specific targeting of the SIN3 corepressor complex (see SIN3A, 607776) by DNA-bound repressors is an important mechanism of gene silencing in eukaryotes. The SIN3 corepressor specifically associates with a diverse group of transcriptional repressors, including members of the MAD family, that play crucial roles in development. Brubaker et al. (2000) determined the nuclear magnetic resonance imaging structure of the complex formed by the PAH2 domain of mammalian Sin3a with the transrepression domain (SIN3-interaction domain, or SID) of human MAD1. They showed that the Sin3a PAH2 domain and the MAD1 SID undergo mutual folding transitions upon complex formation, generating an unusual left-handed, 4-helix bundle structure and an amphipathic alpha helix, respectively. The SID helix is wedged within a deep hydrophobic pocket defined by 2 PAH2 helices.
Luo et al. (2002) showed that RNA interference-mediated suppression of MAD1 function in mammalian cells caused loss of MAD2 kinetochore localization and impairment of the spindle checkpoint. MAD1 and CDC20 (603618) contain MAD2-binding motifs that share a common consensus, and the authors identified a class of MAD2-binding peptides (MBPs) with a similar consensus. Binding of one of these ligands, MBP1, triggered an extensive rearrangement of the tertiary structure of MAD2. MAD2 also underwent a similar striking structural change upon binding to a MAD1 or CDC20 binding motif peptide. These data suggested that, upon checkpoint activation, MAD1 recruits MAD2 to unattached kinetochores and may promote binding of MAD2 to CDC20.
To explore telomerase regulation, Lin and Elledge (2003) employed a general genetic screen in HeLa cells to identify negative regulators of TERT (187270). They discovered 3 tumor suppressor/oncogene pathways involved in TERT repression, including the MAD1/MYC (190080) pathway.
By radiation hybrid analysis, Jin et al. (1999) mapped the human MAD1L1 gene to chromosome 7p22. By interspecific backcross analysis, they mapped the mouse Mad1l1 gene to chromosome 5.
Mosaic Variegated Aneuploidy 7
In a 36-year-old woman, born of unrelated parents, with mosaic variegated aneuploidy-7 (MVA7; 620189), Villarroya-Beltri et al. (2022) identified compound heterozygous nonsense mutations in the MAD1L1 gene (Q66X, 602686.0003 and E628X, 602686.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations resulted in a lack of full-length MAD1L1 protein in patient lymphocytes and reduced levels in lymphocytes from the heterozygous parents. Cells derived from the proband showed a high level of aneuploidy (39 to 43.5%) that was not present in control cells. The parents, who each carried one of the mutations, showed a very low level of chromosomal copy number gains (0.7 and 1.5%, respectively). In vitro studies of patient cells demonstrated mitotic defects in the presence of taxol, indicating dysfunction of the spindle assembly checkpoint (SAC). Single-cell RNA analysis showed evidence of mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFKB (see 164011) signaling both in aneuploid and euploid cells. There were also clonal expansions of T and B-cell subsets, the latter showing transcriptome signatures characteristic of leukemia cells. The proband developed 12 different neoplasias, including 5 malignancies by age 36, illustrating a high cancer susceptibility in this mendelian disorder.
Somatic Mutations
Aneuploidy is a characteristic of most human cancers, and defects of mitotic checkpoints appear to play a role in carcinogenesis. MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability. By RT-PCR-SSCP and nucleotide sequencing, Tsukasaki et al. (2001) performed a mutation search on the MAD1L1 gene in a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma, and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast, and glioblastoma). Eight mutations consisting of missense, nonsense, and frameshift mutations were found, together with a number of nucleotide polymorphisms. All of the alterations in cell lines were heterozygous. The frequency of mutations was relatively high in prostate cancer (2 of 7 cell lines and 2 of 33 tumor specimens). Tsukasaki et al. (2001) placed a mutant truncated MAD1L1 gene from a lymphoma sample into 3 different cell lines and found that it was less inhibitory than wildtype MAD1L1 at decreasing cell proliferation. Coexpression experiments showed that the mutant form had a dominant-negative effect. Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent nocodazole. The results suggested a pathogenic role of mutations in the MAD1L1 gene in various types of human cancer.
In a diffuse large B-cell lymphoma cell line (96227ML), Tsukasaki et al. (2001) identified a 1947C-G transversion in the MAD1L1 gene leading to a premature termination, tyr649 to ter (Y649X), and a truncated protein product. The mutation was present in heterozygous state and appeared to have a dominant-negative effect. It also impaired the mitotic checkpoint function of the gene product.
Tsukasaki et al. (2001) found a relatively high frequency of heterozygous mutations in the MAD1L1 gene in cases of prostate cancer (176807), either in cell lines or in tissue specimens. One of the mutations was a 175C-T transition in the MAD1L1 gene leading to a missense arg59-to-cys (R59C) substitution.
In a 36-year-old woman, born of unrelated parents, with mosaic variegated aneuploidy-7 with inflammation and tumor predisposition (MVA7; 620189), Villarroya-Beltri et al. (2022) identified compound heterozygous nonsense mutations in the MAD1L1 gene: a c.196C-T transition in exon 4, resulting in a gln66-to-ter (Q66X) substitution inherited from the mother, and a c.1882G-T transversion in exon 18, resulting in a glu628-to-ter (E628X; 602686.0004) substitution inherited from the father. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Q66X was found once in the ExAC database (8.304 x 10(-6)), whereas E628X was not present in ExAC or gnomAD. Cells derived from the proband showed a high level of aneuploidy (39 to 43.5%) that was not present in control cells; copy number gains, including of chromosomes 21, 12, and 18, were common. The mutations resulted in a lack of full-length MAD1L1 protein in patient lymphocytes and reduced levels in lymphocytes from the heterozygous parents. In vitro studies of patient cells demonstrated mitotic defects in the presence of taxol, indicating dysfunction of the spindle assembly checkpoint (SAC).
For discussion of the c.1882G-T transversion in the MAD1L1 gene, resulting in a glu628-to-ter (E628X; 602686.0004) substitution that was found in compound heterozygous state in a patient with mosaic variegated aneuploidy-7 with inflammation and tumor predisposition (MVA7; 620189) by Villarroya-Beltri et al. (2022), see 602686.0003.
Brubaker, K., Cowley, S. M., Huang, K., Loo, L., Yochum, G. S., Ayer, D. E., Eisenman, R. N., Radhakrishnan, I. Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex. Cell 103: 655-665, 2000. [PubMed: 11106735] [Full Text: https://doi.org/10.1016/s0092-8674(00)00168-9]
Jin, D.-Y., Kozak, C. A., Pangilinan, F., Spencer, F., Green, E. D., Jeang, K.-T. Mitotic checkpoint locus MAD1L1 maps to human chromosome 7p22 and mouse chromosome 5. Genomics 55: 363-364, 1999. [PubMed: 10049595] [Full Text: https://doi.org/10.1006/geno.1998.5654]
Jin, D.-Y., Spencer, F., Jeang, K.-T. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 93: 81-91, 1998. [PubMed: 9546394] [Full Text: https://doi.org/10.1016/s0092-8674(00)81148-4]
Lin, S.-Y., Elledge, S. J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113: 881-889, 2003. [PubMed: 12837246] [Full Text: https://doi.org/10.1016/s0092-8674(03)00430-6]
Luo, X., Tang, Z., Rizo, J., Yu, H. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Molec. Cell 9: 59-71, 2002. [PubMed: 11804586] [Full Text: https://doi.org/10.1016/s1097-2765(01)00435-x]
Tsukasaki, K., Miller, C. W., Greenspun, E., Eshaghian, S., Kawabata, H., Fujimoto, T., Tomonaga, M., Sawyers, C., Said, J. W., Koeffler, H. P. Mutations in the mitotic check point gene, MAD1L1, in human cancers. Oncogene 20: 3301-3305, 2001. [PubMed: 11423979] [Full Text: https://doi.org/10.1038/sj.onc.1204421]
Villarroya-Beltri, C., Osorio, A., Torres-Ruiz, R., Gomez-Sanchez, D., Trakala, M., Sanchez-Belmonte, A., Mercadillo, F., Hurtado, B., Pitarch, B., Hernandez-Nunez, A., Gomez-Caturla, A., Rueda, D., Perea, J., Rodriguez-Perales, S., Malumbres, M., Urioste, M. Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Sci. Adv. 8: eabq5914, 2022. [PubMed: 36322655] [Full Text: https://doi.org/10.1126/sciadv.abq5914]