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bibliography: 'morinlab.bib' csl: 'NLM.csl' link-citations: true

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.[@morinFrequentMutationHistonemodifying2011; @beaLandscapeSomaticMutations2013] MEF2B has known hotspot mutations that affect multiple distinct domains of the protein.

Experimental Evidence

Thus far, there is limited information about the consequence of MEF2B mutations in DLBCL, FL or MCL. One study showed that MEF2B mutations lead to deregulation of BCL6 expression.[@yingMEF2BMutationsLead]

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
	2	relevance in MCL not firmly established[@beaLandscapeSomaticMutations2013]
	1-EE	high-confidence DLBCL gene [@morinFrequentMutationHistonemodifying2011]
	1-EE	high-confidence FL gene [@morinFrequentMutationHistonemodifying2011]

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


View all variants in GenomePaint hg19 or hg38

MEF2B Expression

References