Online Mendelian Inheritance in Man (OMIM)

Alternative titles; symbols

RHOMBOTIN 1; RBTN1
RHOMBOSINE; RHOM1
T-CELL TRANSLOCATION GENE 1; TTG1

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
11p15.4	Leukemia, T-cell acute lymphoblastic	186921		2

.0001   LMO1 POLYMORPHISM

LMO1, IVS1, G-T ({dbSNP rs2168101})
SNP: rs2168101, gnomAD: rs2168101, ClinVar: RCV000207127, RCV004586626

In a genomewide association study, Wang et al. (2011) identified common polymorphisms at the LMO1 gene locus that were highly associated with neuroblastoma susceptibility (see NBLST7, 616792) and oncogenic addiction to LMO1 in the tumor cells. In a follow-up study to investigate the causal DNA variant at the LMO1 locus and the mechanism by which it leads to neuroblastoma tumorigenesis, Oldridge et al. (2015) showed that a SNP in intron 1 of the LMO1 gene, rs2168101G-T, is the most highly associated variant (combined p = 7.47 x 10(-29), OR 0.65, 95% CI 0.60-0.70), and resides in a superenhancer defined by extensive acetylation of histone H3 lysine-27 (H3K27). The ancestral G allele that is associated with tumor formation resides in a conserved GATA transcription factor-binding motif. Chromatin immunoprecipitation sequencing (ChIP-seq) using a GATA3 (131320) antibody in neuroblastoma cell lines demonstrated robust GATA3 binding at rs2168101 in cell lines containing the G allele, but not in lines containing the T allele. Using mRNA sequencing, Oldridge et al. (2015) found significantly higher LMO1 expression in G/G versus G/T genotype tumors. The authors showed that the protective TATA allele is associated with decreased total LMO1 expression (p = 0.028) in neuroblastoma primary tumors, and ablates GATA3 binding (p less than 0.0001). Oldridge et al. (2015) demonstrated allelic imbalance favoring the G-containing strand in tumors heterozygous for this SNP, as demonstrated both by RNA sequencing and reporter assays. ChIP-seq demonstrated extensive H3K27 acetylation in the first intron of LMO1 across rs2168101 in neuroblastoma cell lines carrying the G allele that was not observed in a cell line carrying the T allele. The protective T allele is common in Europeans (CEU HapMap, 28%) and East Asians (CHB+JPT HapMap, 32%) but is rare or absent in Africans, indicating recent expansion of this allele in non-African human populations. Oldridge et al. (2015) suggested that the rarity of the protective T allele in African populations and its relative depletion in African Americans may partially explain the more aggressive clinical course in African American children.

1. Angel, J. M., Moore, J. L., Pelphrey, A., Richie, E. R. The mouse homolog of the rhombotin (Ttg-1) gene maps on chromosome 7 distal to the beta-globin (Hbb) locus. Mammalian Genome 4: 281-282, 1993. [PubMed: 8099513] [Full Text: https://doi.org/10.1007/BF00417437]

2. Boehm, T., Baer, R., Lavenir, I., Forster, A., Waters, J. J., Nacheva, E., Rabbitts, T. H. The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C-delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. EMBO J. 7: 385-394, 1988. [PubMed: 3259177] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb02825.x]

3. Boehm, T., Foroni, L., Kaneko, Y., Perutz, M. F., Rabbitts, T. H. The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc. Nat. Acad. Sci. 88: 4367-4371, 1991. [PubMed: 2034676] [Full Text: https://doi.org/10.1073/pnas.88.10.4367]

4. Boehm, T., Foroni, L., Kennedy, M., Rabbitts, T. H. The rhombotin gene belongs to a class of transcriptional regulators with a potential novel protein dimerisation motif. Oncogene 5: 1103-1105, 1990. [PubMed: 2115645]

5. Greenberg, J., Boehm, T., Surane, A., Keynes, R., Sofronew, M., Rabbitts, T. H. A human T cell translocation involving chromosome 11p15 identifies a gene expressed in developing rhombomeres of the mouse hind brain. (Abstract) Cytogenet. Cell Genet. 51: 1008 only, 1989.

6. Oldridge, D. A., Wood, A. C., Weichert-Leahey, N., Crimmins, I., Sussman, R., Winter, C., McDaniel, L. D., Diamond, M., Hart, L. S., Zhu, S., Durbin, A. D., and 16 others. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528: 418-421, 2015. [PubMed: 26560027] [Full Text: https://doi.org/10.1038/nature15540]

7. Wang, K., Diskin, S. J., Zhang, H., Attiyeh, E. F., Winter, C., Hou, C., Schnepp, R. W., Diamond, M., Bosse, K., Mayes, P. A., Glessner, J., Kim, C., Abraham, B. J., and 21 others. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 469: 216-220, 2011. [PubMed: 21124317] [Full Text: https://doi.org/10.1038/nature09609]