HGNC Approved Gene Symbol: MXI1
SNOMEDCT: 399068003, 404037002; ICD10CM: C61; ICD9CM: 185;
Cytogenetic location: 10q25.2 Genomic coordinates (GRCh38): 10:110,207,605-110,287,365 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.2 | Neurofibrosarcoma, somatic | 3 | ||
| Prostate cancer, somatic | 176807 | 3 |
The MAD (600021) and MXI1 genes encode basic helix-loop-helix leucine zipper transcription factors that bind MAX (154950) in vitro, forming a sequence-specific DNA-binding complex similar to the MYC-MAX heterodimer. MXI1 and MAD may antagonize MYC function and are candidate tumor suppressor genes (Edelhoff et al., 1994).
Zervos et al. (1993) isolated the MXI1 as a protein that specifically interacts with MAX. The MXI1 protein contains a bHLH-ZIP motif that is similar to that found in Myc family proteins. MXI1 interacts specifically with MAX to form heterodimers that efficiently bind to the Myc-MAX consensus recognition site. When bound to DNA by a LexA moiety in yeast, MXI1 does not stimulate transcription.
Albarosa et al. (1995) concluded that the coding sequence of MXI1 has an open reading frame that is 28 codons shorter at the 3-prime end than previously described.
Wechsler et al. (1996) showed that MXI1 contains 6 exons and spans approximately 60 kb.
Edelhoff et al. (1994) mapped the MXI1 gene to human chromosome 10q25 and to mouse chromosome 19 at region D by fluorescence in situ hybridization (FISH). A second site of hybridization on mouse chromosome 2 at region C was thought to represent either a pseudogene or a related sequence. By FISH, Wechsler et al. (1994) mapped the MXI1 gene to 10q24-q25. Shapiro et al. (1994) confirmed the assignments of the MAD and MXI1 genes to chromosomes 2p13-p12 and 10q24-q25, respectively, by somatic cell mapping and FISH.
In the mouse, Steingrimsson et al. (1995) mapped the Mxi1 gene, as well as those for 4 other bHLH-ZIP transcription factors, by interspecific backcross analysis. An Mxi1 gene was found to reside on mouse chromosome 19 in an area known to have homology of synteny to human 10q.
Albarosa et al. (1995) found an AAAAC polymorphic repeat in the 3-prime noncoding region of the gene. Using this polymorphism, they demonstrated loss of heterozygosity in all of 9 glioblastomas and in none of 6 anaplastic astrocytomas. Glioblastoma multiforme (137800) demonstrates chromosome 10 changes in a majority of instances.
Since the MXI1 protein negatively regulates MYC oncoprotein activity, it potentially serves a tumor suppressor function. MXI1 maps to a region of chromosome 10 that is deleted in some cases of prostate cancer (176807). This prompted Eagle et al. (1995) to do studies in which they demonstrated mutations in the retained MXI1 allele in 4 primary prostate tumors with 10q24-q25 deletions. Two tumors contained inactivating mutations, whereas 2 others contained the identical missense mutation. Fluorescence in situ hybridization also demonstrated loss of one MXI1 allele in an additional tumor lacking chromosome 10 abnormalities. MXI1 thus displays allelic loss and mutation in some cases of prostate cancer that may contribute to the pathogenesis or neoplastic evolution of this common malignancy. These findings satisfy the Knudson 2-hit hypothesis.
One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25 has been observed, suggesting the presence of a tumor suppressor gene at that site. Prochownik et al. (1998) prospectively evaluated prostate tumors for loss of MXI1 by FISH and cytogenetic techniques. Of 40 tumors, 21 (53%) demonstrated loss of a single MXI1 allele, as determined by FISH. In 10 cases with cytogenetically normal long arms of chromosome 10, but with FISH-documented deletion of MXI1, 8 mutations of MXI1 were identified. Five of the mutant proteins were incapable of binding DNA in association with MAX. Prochownik et al. (1998) concluded that MXI1 gene loss in prostate cancer is common and most frequently involves a cytogenetically undetectable deletion.
MXI1 appears to regulate MYC function negatively and therefore is a potential tumor suppressor gene. Li et al. (1999) screened for MXI1 mutations in solid tumors, including 4 neurofibrosarcomas, and also examined 29 human tumor cell lines. They discovered a missense mutation, GCA to GTA (ala54 to val; 600020.0004), in exon 2 in a neurofibrosarcoma patient; they found 2 different missense mutations in a second neurofibrosarcoma patient, and 3 amino acid substitutions in a third. In the last patient, loss of heterozygosity was also demonstrated. Neurofibrosarcoma is known to develop in patients with neurofibromatosis type I (NF1; 162200). Li et al. (1999) suggested that MXI1 mutations may play a role in the pathogenesis of neurofibrosarcoma in NF1; the second case of 2 mutations in exon 5 occurred in a patient who also had NF1.
MXI1 belongs to the family of proteins that function as potent antagonists of MYC oncoproteins. This antagonism relates to their ability to compete with MYC for the protein MAX and for consensus DNA binding sites and to recruit Sin3 proteins (see SIN3A; 607776) and their associated corepressors. Schreiber-Agus et al. (1998) disrupted the Mxi1 open reading frame in transgenic mice by eliminating an exon required for the production of the 2 mouse Mxi1 isoforms. They showed that the mice lacking Mxi1 exhibit progressive multisystem abnormalities. The mice also showed increased susceptibility to tumorigenesis either following carcinogen treatment or when also deficient in INK4A (600160). This cancer-prone phenotype may correspond with the enhanced ability of several MXI1-deficient cell types, including prostatic epithelium, to proliferate. The results show that MXI1 is involved in the homeostasis of differentiated organ systems, acts as a tumor suppressor in vivo, and engages the MYC network in a functionally relevant manner. In histologic studies of the mice, Schreiber-Agus et al. (1998) focused particularly on organs that normally express high or sustained levels of Mxi1, e.g., brain, spleen, kidney, and liver, and on tissue types that are susceptible to tumorigenesis when a putative tumor suppressor is lost from the 10q24-q26 region; for example, the spleen and thymus are susceptible to T-cell leukemia, the prostatic epithelium to prostate cancer, and the brain to glioblastoma multiforme when the 10q24-q26 region is mutated.
In a prostate cancer (176807) tumor, Eagle et al. (1995) found loss of a single alanine at codon 140 or 141, converting AAG (lys) to AGT (ser) in the ZIP-encoding exon. The frameshift resulted in loss of the terminal leucine residue of the ZIP domain as well as loss of all additional downstream amino acid sequences, including those comprising the last 2 alpha-helical turns of the ZIP domain. This was a presumably inactivating mutation.
In a prostate cancer (176807) tumor, Eagle et al. (1995) observed a T-to-C transition in the invariant GT dinucleotide of the splice donor site of the ZIP-encoding exon.
In prostate cancer (176807) tumors from 2 different patients, Eagle et al. (1995) found the same mutation, an A-to-C transversion in the second nucleotide of codon 152 resulting in the nonconservative substitution of alanine (GCG) for glutamic acid (GAG).
Li et al. (1999) identified MXI1 mutations in 3 of 4 neurofibrosarcoma patients. One of the mutations was a change from GCA to GTA (ala54 to val) in exon 2. Neurofibrosarcoma is known to develop in patients with neurofibromatosis type I (162200).
Albarosa, R., DiDonato, S., Finocchiaro, G. Redefinition of the coding sequence of the MXI1 gene and identification of a polymorphic repeat in the 3-prime non-coding region that allows the detection of loss of heterozygosity of chromosome 10q25 in glioblastomas. Hum. Genet. 95: 709-711, 1995. [PubMed: 7789959] [Full Text: https://doi.org/10.1007/BF00209493]
Eagle, L. R., Yin, X., Brothman, A. R., Williams, B. J., Atkin, N. B., Prochownik, E. V. Mutation of the MXI1 gene in prostate cancer. Nature Genet. 9: 249-255, 1995. [PubMed: 7773287] [Full Text: https://doi.org/10.1038/ng0395-249]
Edelhoff, S., Ayer, D. E., Zervos, A. S., Steingrimsson, E., Jenkins, N. A., Copeland, N. G., Eisenman, R. N., Brent, R., Disteche, C. M. Mapping of two genes encoding members of a distinct subfamily of MAX interacting proteins: MAD to human chromosome 2 and mouse chromosome 6, and MXI1 to chromosome 10 and mouse chromosome 19. Oncogene 9: 665-668, 1994. [PubMed: 8290278]
Li, X.-J., Wang, D.-Y., Zhu, Y., Guo, R.-J., Wang, X.-D., Lubomir, K., Mukai, K., Sasaki, H., Yoshida, H., Oka, T., Machinami, R., Shinmura, K., Tanaka, M., Sugimura, H. Mxi1 mutations in human neurofibrosarcomas. Jpn. J. Cancer Res. 90: 740-746, 1999. [PubMed: 10470286] [Full Text: https://doi.org/10.1111/j.1349-7006.1999.tb00809.x]
Prochownik, E. V., Grove, L. E., Deubler, D., Zhu, X. L., Stephenson, R. A., Rohr, L. R., Yin, X., Brothman, A. R. Commonly occurring loss and mutation of the MXI1 gene in prostate cancer. Genes Chromosomes Cancer 22: 295-304, 1998. [PubMed: 9669667]
Schreiber-Agus, N., Meng, Y., Hoang, T., Hou, H., Jr., Chen, K., Greenberg, R., Cordon-Cardo, C., Lee, H.-W., DePinho, R. A. Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. Nature 393: 483-487, 1998. [PubMed: 9624006] [Full Text: https://doi.org/10.1038/31008]
Shapiro, D. N., Valentine, V., Eagle, L., Yin, X., Morris, S. W., Prochownik, E. V. Assignment of the human MAD and MXI1 genes to chromosomes 2p12-p13 and 10q24-q25. Genomics 23: 282-285, 1994. [PubMed: 7829091] [Full Text: https://doi.org/10.1006/geno.1994.1496]
Steingrimsson, E., Sawadogo, M., Gilbert, D. J., Zervos, A. S., Brent, R., Blanar, M. A., Fisher, D. E., Copeland, N. G., Jenkins, N. A. Murine chromosomal location of five bHLH-Zip transcription factor genes. Genomics 28: 179-183, 1995. [PubMed: 8530024] [Full Text: https://doi.org/10.1006/geno.1995.1129]
Wechsler, D. S., Hawkins, A. L., Li, X., Jabs, E. W., Griffin, C. A., Dang, C. V. Localization of the human Mxi1 transcription factor gene (MXI1) to chromosome 10q24-q25. Genomics 21: 669-672, 1994. [PubMed: 7959753] [Full Text: https://doi.org/10.1006/geno.1994.1336]
Wechsler, D. S., Shelly, C. A., Dang, C. V. Genomic organization of human MXI1, a putative tumor suppressor gene. Genomics 32: 466-470, 1996. [PubMed: 8838813] [Full Text: https://doi.org/10.1006/geno.1996.0144]
Zervos, A. S., Gyuris, J., Brent, R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell 72: 223-232, 1993. Note: Erratum: Cell 79: 389 only, 1994. [PubMed: 8425219] [Full Text: https://doi.org/10.1016/0092-8674(93)90662-a]