MTX2

protein-coding

metaxin 2, the group of Metaxins

Gene summary

The protein encoded by this gene is highly similar to the metaxin 2 protein from mouse, which has been shown to interact with the mitochondrial membrane protein metaxin 1. Because of this similarity, it is thought that the encoded protein is peripherally associated with the cytosolic face of the outer mitochondrial membrane, and that it is involved in the import of proteins into the mitochondrion. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Jun 2009]

MANE transcript

NM_006554.5

Inheritance

ClinVar variants

P:9U:41B:2

Top phenotype

Mandibuloacral dysplasia progeroid syndrome

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr2:176,269,395-176,338,025

External References & Databases

Ensembl (ENSG00000128654)

Transcript & Mutation Effects

hg38 • Region Span ~68.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mandibuloacral dysplasia progeroid syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030880

Submitter: Labcorp Genetics (formerly Invitae)

mandibuloacral dysplasia progeroid syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030880

Submitter: ClinGen

*MTX2* was first reported in relation to autosomal recessive mandibuloacral dysplasia progeroid syndrome (MDPS; OMIM # 619127) in 2020 (Elouej et al., PMID: 32917887). MDPS is a severe laminopathy-like disorder characterized by by dysmorphic facial features, lipodystrophy, skin changes, clavicular hypoplasia, acral osteolysis, and normal intelligence with an unknown prevalence. *MTX2* encodes the metaxin 2 protein which is located at the outer mitochondrial membrane (OMM) and faces the cytosolic compartment through direct interaction with its partner Metaxin-1 (MTX1). It is involved in protein translocation into mitochondria. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Nine unique loss of function variants (frameshift, start loss, splice variants) that have been reported in 8 probands in 3 publications are included in this curation (PMID: 32917887; Dogan et al 2022, PMID: 36269149; Li et al 2024, PMID: 38250156). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationshipis also supported by expression studies, t animal models, rescue experiments, and in-vitro functional assays. Experimentally, *MTX2* deficiency is demostrated to result in loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment, which may account for poor growth, hypotonia, muscle weakness, skeletal abnormalities, nephrotic proteinuria and glomerulopathy. In summary, there is definitive evidence supporting the relationship between *MTX2* and autosomal recessive mandibuloacral dysplasia progeroid syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Syndromic Disorders GCEP on the meeting date June 5, 2024 (SOP Version 10).

mandibuloacral dysplasia progeroid syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030880

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mandibuloacral dysplasia progeroid syndromeAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: Among other findings, individuals may have early-onset respiratory infections, and awareness may allow prompt diagnosis and management; Cardiovascular manifestations, including cardiomyopathy and valvular anomalies, have been described, and awareness may allow prompt diagnosis and management

Refs: 32917887

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTX2 variants in ClinVar

15 Conditions Cataloged

not specifiedTotal: 29

Mandibuloacral dysplasia progeroid syndromeTotal: 9

Progeroid mandibuloacral dysplasiaTotal: 4

not providedTotal: 2

MTX2-related conditionTotal: 2

MicrognathiaTotal: 1

Hypertensive disorderTotal: 1

Postnatal growth retardationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006554.5. 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			2 clinvar		1 clinvar	3
missense			32 clinvar	1 clinvar		33
nonsense						0
start loss	1 clinvar					1
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)	4 clinvar	2 clinvar	7 clinvar			13
Total	7	2	41	1	1	52

Highest pathogenic variant AF is 0.0000019554166

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006554.5	RefSeq	NP_006545.1	10	MANE Select
ENST00000249442.11	Ensembl	ENSP00000249442.6	10	MANE Select
NM_001006635.3	RefSeq	NP_001006636.1	10	Standard
NM_001319097.2	RefSeq	NP_001306026.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

mitochondrial transport
protein transport

Molecular Function

protein binding

Cellular Component

mitochondrial sorting and assembly machinery complex
nucleolus
mitochondrion
mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000249442
Coding exons: 10
Length: 68631
Individuals with no LoFs: 125514
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125531
p: 0.0000677

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.838	104	131	0.794	0.00000606	1707
Missense (PolyPhen)		23	31.609	0.72763		438
Synonymous	-1.86	60	44.2	1.36	0.00000209	469
Loss of Function	2.55	6	17.5	0.343	7.41e-7	215

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000040	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in transport of proteins into the mitochondrion. {ECO:0000269|PubMed:10381257}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.609
RVIS EVS: 0.06
RVIS percentile EVS: 58.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.427

Gene Damage Prediction

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