MDM4

protein-coding

MDM4 regulator of p53, the group of Ring finger proteins

Gene summary

This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_002393.5

Inheritance

ClinVar variants

U:50B:10

Top phenotype

Bone marrow failure syndrome 6

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:204,516,379-204,558,120

External References & Databases

Ensembl (ENSG00000198625)

Transcript & Mutation Effects

hg38 • Region Span ~41.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

bone marrow failure syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000159

Submitter: PanelApp Australia

bone marrow failure syndrome 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030015

Submitter: Labcorp Genetics (formerly Invitae)

bone marrow failure syndrome 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030015

Submitter: ClinGen

MDM4 was first reported in relation to autosomal dominant bone marrow syndrome 6 in 2020 (Toufektchan et al., 2020 PMID: 32300648). Patients present with bone marrow hypocellularity, neutropenia, and other variable features such as gastrointestinal symptoms, B cell deficiency, cytopenia/aplastic anemia, atrial septal defect, premature birth, and head and neck squamous cell carcinoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: bone marrow failure syndrome 6 (OMIM:618849), dyskeratosis congenita-like syndrome, and acute myeloid leukaemia/myelodysplastic syndrome. Four variants (3 missense, 1 canonical splice site) that have been reported in four probands in 3 publications and 1 ClinVar submitter (PMIDs: 29146883, 32098966, 32300648, SCV002058868.1) are included in this curation. The mechanism of pathogenicity is reported to be loss of function which results in p53 increased activity (PMID: 32300648). This gene-disease relationship is also supported by experimental evidence. The c.1361C>T (p.Thr454Met) mutant RING domain had fully retained its capacity to bind ATP specifically but exhibited an altered capacity to interact with the MDM2 RING domain in a yeast two-hybrid assay (PMID: 32300648). Additionally, transfection of this mutation into human U2OS cells resulted in decreased levels of the mutant protein and lack of inhibition of TP53 (PMID: 32300648). In addition, a Mdm4T454M/T454M MEF cell culture model showed increased p53 activity and short telomeres (PMID: 32300648 ). The Mdm4+/T454M p53+/Δ31 mouse model exhibited bone marrow hypocellularity in the sternum sections of the moribund animals, intense skin hyperpigmentation, heart hypertrophy, thymic hypoplasia, and were much smaller than their littermates (PMID: 32300648). An additional mouse model revealed that Mdm4 is required for generating high erythropoietic rates during definitive fetal erythropoiesis (PMID: 17105817). Lastly, biochemical function studies demonstrated that Mdm4 and Mdm2 cooperate to inhibit p53 activity in vivo (PMID: 16492744). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 12/10/2024 (SOP Version 11).

Clinical Genomic Database (CGD)

Bone marrow failure syndrome 6AD

Manifestation: Hematologic; Oncologic

Intervention: Hematologic; Oncologic

Rationale: Individuals (including based on family history) have been described with bone marrow failure as well as apparent increased risk of malignancies, and awareness may allow prompt management

Refs: 32300648

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MDM4 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 45

not providedTotal: 12

Bone marrow failure syndrome 6Total: 5

MDM4-related disorderTotal: 2

Pfeiffer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002393.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				3 clinvar	2 clinvar	5
missense			48 clinvar	4 clinvar	1 clinvar	53
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	0	50	7	3	60

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002393.5	RefSeq	NP_002384.2	10	MANE Select
ENST00000367182.8	Ensembl	ENSP00000356150.3	10	MANE Select
NM_001204171.2	RefSeq	NP_001191100.1	9	Standard
NM_001204172.2	RefSeq	NP_001191101.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

p53 signaling pathway - Homo sapiens (human)
MicroRNAs in cancer - Homo sapiens (human)
Signaling Pathways in Glioblastoma
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

negative regulation of transcription by RNA polymerase II
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
cell population proliferation
negative regulation of cell population proliferation
protein ubiquitination

Molecular Function

protein binding
zinc ion binding
enzyme binding
ubiquitin protein ligase activity

Cellular Component

nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367182
Coding exons: 10
Length: 57361
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.71	181	259	0.700	0.0000126	3230
Missense (PolyPhen)		33	83.031	0.39744		1066
Synonymous	-0.723	101	92.2	1.10	0.00000493	894
Loss of Function	4.79	0	26.7	0.00	0.00000139	326

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. {ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:16511572}.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.501
RVIS EVS: 0.08
RVIS percentile EVS: 60.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium