MEF2B - morinlab/LLMPP GitHub Wiki

MEF2B

Overview

MEF2B is one of a number of genes affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. MEF2B mutations are observed in a significant subset of follicular lymphoma cases, as well as in other B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and MCL.1 MEF2B has known hotspot mutations that affect multiple distinct domains of the protein.

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%%
timeline
    title Publication timing
      2011-07-27 : Morin : DLBCL
      2013-11-05 : Bea : MCL

Relevance tier by entity

Entity Tier Description
MCL 2 relevance in MCL not firmly established
BL 2-a aSHM target; Although recurrent, the relevance of mutations in BL is tenuous
DLBCL 1-a aSHM target and high-confidence DLBCL gene
FL 1-a aSHM target and high-confidence FL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity source frequency (%)
BL GAMBL genomes+capture 1.39
BL Thomas cohort 0.80
BL Panea cohort 3.00
DLBCL GAMBL genomes 11.28
DLBCL Schmitz cohort 9.79
DLBCL Reddy cohort 5.91
DLBCL Chapuy cohort 5.56
FL GAMBL genomes 12.93
MCL GAMBL genomes 5.69

Mutation pattern and selective pressure estimates

Entity aSHM Significant selection dN/dS (missense) dN/dS (nonsense)
BL Yes No 2.449 0.000
DLBCL Yes Yes 22.928 171.945
FL Yes Yes 111.098 0.000

aSHM regions

chr_name hg19_start hg19_end region regulatory_comment
chr19 19279635 19281441 TSS active_promoter

MEF2B Hotspots

DNA-Binding Domain (MADS-box and MEF2 Domain):

R24 (Arginine 24) A recurrent hotspot mutation. This position is located within the MADS-box domain, which is crucial for DNA binding and dimerization with other MEF2 family members.

R30 (Arginine 30) Another recurrent hotspot in the MADS-box domain. Mutations at this site can disrupt DNA binding and affect the transcriptional activity of MEF2B.

Transcriptional Activation Domain:

N81 (Asparagine 81) A mutation hotspot within the transcriptional activation domain. Alterations at this position can enhance the transcriptional activity of MEF2B, contributing to the overexpression of target genes involved in cell survival and proliferation.

Functional Impact of MEF2B Mutations

Altered Transcriptional Activity:

Mutations in the DNA-binding domain, such as those at R24 and R30, can alter the binding affinity and specificity of MEF2B for its target DNA sequences. This can lead to changes in the expression of genes that are critical for cell growth, differentiation, and survival. Mutations in the transcriptional activation domain, like N81, can enhance the ability of MEF2B to activate transcription, which may lead to the upregulation of oncogenes and survival pathways.

MEF2B Hot Spots from GAMBL

Chromosome Coordinate (hg19) ref>alt HGVSp
chr19 19260066 T>C H76R
chr19 19260064 C>T E77K
chr19 19260050 G>T N81K
chr19 19260045 T>G D83A
chr19 19260045 T>C D83G
chr19 19260045 T>A D83V
chr19 19260042 A>G I84T

View coding variants in ProteinPaint hg19 or hg38

![](images/proteinpaint/MEF2B_NM_001145785.svg images/proteinpaint/MEF2B_zoom.svg)

View all variants in GenomePaint hg19 or hg38

MEF2B Expression

References

  1. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJM, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul 27;476(7360):298–303. PMCID: PMC3210554
  2. Beà S, Valdés-Mas R, Navarro A, Salaverria I, Martín-Garcia D, Jares P, Giné E, Pinyol M, Royo C, Nadeu F, Conde L, Juan M, Clot G, Vizán P, Croce LD, Puente DA, López-Guerra M, Moros A, Roue G, Aymerich M, Villamor N, Colomo L, Martínez A, Valera A, Martín-Subero JI, Amador V, Hernández L, Rozman M, Enjuanes A, Forcada P, Muntañola A, Hartmann EM, Calasanz MJ, Rosenwald A, Ott G, Hernández-Rivas JM, Klapper W, Siebert R, Wiestner A, Wilson WH, Colomer D, López-Guillermo A, López-Otín C, Puente XS, Campo E. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. PNAS. 2013 Nov 5;110(45):18250–18255. PMID: 24145436
⚠️ **GitHub.com Fallback** ⚠️