MATR3

protein-coding

matrin 3, the group of Small nucleolar RNA protein coding host genes

Gene summary

This gene encodes a nuclear matrix protein, which is proposed to stabilize certain messenger RNA species. Mutations of this gene are associated with distal myopathy 2, which often includes vocal cord and pharyngeal weakness. Alternatively spliced transcript variants, including read-through transcripts composed of the upstream small nucleolar RNA host gene 4 (non-protein coding) and matrin 3 gene sequence, have been identified. Pseudogenes of this gene are located on chromosomes 1 and X. [provided by RefSeq, Aug 2013]

Previous symbols:

MPD2

MANE transcript

NM_018834.6

Inheritance

ClinVar variants

P:1U:307B:159

Top phenotype

Amyotrophic lateral sclerosis 21

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:139,293,674-139,331,677

External References & Databases

Ensembl (ENSG00000015479)

Transcript & Mutation Effects

hg38 • Region Span ~38.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 21MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011632

Submitter: Ambry Genetics

amyotrophic lateral sclerosis type 21STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011632

Submitter: PanelApp Australia

distal myopathy with vocal cord weaknessDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018951

Submitter: ClinGen

Variants in *MATR3* were first reported as a cause of autosomal dominant distal myopathy with vocal cord weakness in 2009 (Senderek J, et al., 2009, PMID: 19344878). The *MATR3* gene encodes matrin-3, a highly conserved nuclear matrix protein that binds and interacts with nucleic acids (Belgrader et al., 1991; Hibino et al., 2006). It plays a role in RNA transcription and processing, as well as mRNA stabilization (Hibino et al., 2006). Structurally, the protein includes two zinc finger domains that interact with DNA, along with two domains that bind RNA (Belgrader et al., 1991; Hibino et al., 2006; Salton et al., 2011; Johnson et al., 2014). Heterozygous variants in the *MATR3* gene are asserted to casue amyotrophic lateral sclerosis (ALS) type 21 and distal myopathy with vocal cord and pharyngeal weakness (VCPDM) inherited in an autosomal dominant manner (Senderek et al., 2009; Johnson et al., 2014); the ALS GCEP has lumped these into a single curation for distal myopathy based on an overlap of phenotypes and molecular mechanism. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. At least 12 missense variants have been reported in 20 probands from 17 publications (PMIDs: 24686783, 28029397, 26493020, 25771394, 26199109, 26708275, 31432357, 31475037, 19344878, 25154462, 25185957, 25952333, 32361838, 29628183, 34659085, 35812165, 39192891). The Ser85Cys variant is recurrent and predominantly found in patients with distal myopathy, however one family was retrospectively diagnose with ALS (PMID: 24686783). Segregation of this variant across 39 patients from 5 families was included in this curation. Experimentally, this gene-disease relationship is supported by the role of *MATR3* as an RNA-binding protein involved in mRNA transport and nuclear export, processes known to be impacted in ALS (PMID: 29109432). Additionally, *MATR3* has been found to bind and interact with critical ALS proteins TDP-43 (PMID: 24686783, 29109432), FUS (PMID: 29109432) and C9orf92 (PMID: 33129345). Further support is provided by a mouse models including overexpression and CRISPR-cas9 knock-in models (PMID: 33082323) that partially recapitulates phenotypic and pathological features. In summary, there is definitive evidence to support the relationship between *MATR3* and autosomal dominant distal myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

amyotrophic lateral sclerosis type 21STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011632

Submitter: Labcorp Genetics (formerly Invitae)

distal myopathy with vocal cord weaknessSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018951

Submitter: Orphanet

amyotrophic lateral sclerosis type 21MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011632

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 21AD

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9837826; 19344878; 24686783; 25154462

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MATR3 variants in ClinVar

8 Conditions Cataloged

Amyotrophic lateral sclerosis type 21Total: 507

not providedTotal: 73

Inborn genetic diseasesTotal: 67

MATR3-related disorderTotal: 62

not specifiedTotal: 20

Amyotrophic lateral sclerosisTotal: 4

Distal myopathy with vocal cord weaknessTotal: 1

NeurodegenerationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018834.6. 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			4 clinvar	143 clinvar	3 clinvar	150
missense	1 clinvar		291 clinvar	13 clinvar		305
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	1	0	307	156	3	467

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 154 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018834.6	RefSeq	NP_061322.2	14	MANE Select
ENST00000394805.8	Ensembl	ENSP00000378284.3	14	MANE Select
NM_001194954.2	RefSeq	NP_001181883.1	14	Standard
NM_001194955.2	RefSeq	NP_001181884.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in leukocytes - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
antisense pathway

Biological Process

activation of innate immune response
posttranscriptional regulation of gene expression
innate immune response

Molecular Function

RNA binding
structural molecule activity
protein binding
zinc ion binding
miRNA binding

Cellular Component

nuclear inner membrane
membrane
nuclear matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394805
Coding exons: 14
Length: 57920
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125676
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.73	289	452	0.639	0.0000230	5613
Missense (PolyPhen)		100	235.26	0.42505		3004
Synonymous	0.0141	159	159	0.999	0.00000845	1568
Loss of Function	5.68	0	37.5	0.00	0.00000183	507

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. In association with the SFPQ-NONO heteromer may play a role in nuclear retention of defective RNAs. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). May bind to specific miRNA hairpins (PubMed:28431233). {ECO:0000269|PubMed:11525732, ECO:0000269|PubMed:28431233, ECO:0000269|PubMed:28712728}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 21 (ALS21) [MIM:606070]: A neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia. {ECO:0000269|PubMed:19344878, ECO:0000269|PubMed:24686783, ECO:0000269|PubMed:25771394, ECO:0000269|PubMed:26199109}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.217
RVIS EVS: -0.65
RVIS percentile EVS: 16.36

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

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