TARDBP

protein-coding

TAR DNA binding protein, the group of RNA binding motif containing

Gene summary

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. [provided by RefSeq, Jul 2008]

MANE transcript

NM_007375.4

Inheritance

ClinVar variants

P:32U:99B:64

Top phenotype

Amyotrophic lateral sclerosis 10, with or without frontotemporal dementia

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr1:11,012,344-11,030,528

External References & Databases

Ensembl (ENSG00000120948)

Transcript & Mutation Effects

hg38 • Region Span ~18.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012790

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosis type 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012790

Submitter: Labcorp Genetics (formerly Invitae)

inclusion body myositisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007827

Submitter: Broad Center for Mendelian Genomics

amyotrophic lateral sclerosis type 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012790

Submitter: ClinGen

TARDBP was first reported in autosomal dominant amyotrophic lateral sclerosis 10 (ALS) in 2008 (Sreedharan J, et al, 2008, PMID:18309045). Following the discovery of the TDP-43 protein as the principle component of ALS hallmark ubiquitinated protein inclusions within affected motor neurons (Neumann M, et al, 2006, PMID:17023659 and Arai T, et al 2006, PMID: 17084815), the authors investigated the TARDBP gene endoding this TDP-43 protein as a candidate gene in a cohort of index cases with familial ALS. Screening of TRADBP in this cohort identified missense mutation in a Caucasian family segregating with disease in a total of five affected family members across two generations. Genome-wide SNP-based linkage analysis including a total of 23 family members identified linkage to 1p36 with a parametric multipoint LOD score of 2.04. Fine mapping confirmed linkage with a maximal two-point LOD score of 2.73 at D1S450 and a highly significant multipoint lod score of 2.93. Extended cohort screening further identified a further two TARDBP missense mutations, each identified in a single sporadic ALS case. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. TARDBP encodes the TAR DNA binding protein 43 (TDP-43), and while the exact function of thise RNA/DNA protein is unknown, it is known to play roles in transcriptional repression and alternative splicing (PMID: 11470789). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 60 mutations in TARDBP have been implicated in ALS, including single point mutations and small insertion/deletions, with the majority of these mutations falling in the final exon 6 of this gene (reviewed in PMID: 30837838, literature search in PMID: 32409511). A number of TDP-43 related phenotypes are reported among ALS patients, including its aggregation into protein inclusions, depletion in the nucleus and mislocalisation to the cytoplasm and sequestration into stress granules (reviewed in PMID: 30837838). Experimentally, this disease-gene relationship is also supported by a number of animal models that recapitulate various ALS related phenotypes. More genetic and experimental evidence is available in the literature, however the maximum score of 18pts has been reached. In summary TARDBP is definitively associated with autosomal dominant amyotrophic lateral sclerosis 10. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

frontotemporal dementia with motor neuron diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017161

Submitter: Orphanet

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

amyotrophic lateral sclerosis type 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012790

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 10, with or without frontotemporal dementiaAD

Manifestation: Neurologic

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: 17036243; 18288693; 18309045; 18372902; 18396105; 18438952; 18779421; 19224587; 19350673; 19609911; 20697052; 21220647; 21956716; 22292843; 22398199; 22456481; 22539580; 22722621; 24300238

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TARDBP variants in ClinVar

12 Conditions Cataloged

Amyotrophic lateral sclerosis type 10Total: 168

FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATEDTotal: 153

not providedTotal: 56

Inborn genetic diseasesTotal: 56

TARDBP-related disorderTotal: 22

not specifiedTotal: 8

Motor neuron diseaseTotal: 3

FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATEDTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007375.4. 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	61 clinvar	2 clinvar	66
missense	9 clinvar	22 clinvar	86 clinvar	1 clinvar		118
nonsense		1 clinvar	6 clinvar			7
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	9	23	99	62	2	195

Highest pathogenic variant AF is 0.000062577215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007375.4	RefSeq	NP_031401.1	5	MANE Select
ENST00000240185.8	Ensembl	ENSP00000240185.4	5	MANE Select
ENST00000315091.7	Ensembl	ENSP00000313129.3	6	Standard
ENST00000315091.8	Ensembl	ENSP00000313129.3	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tardbp	Danio rerio	Structure: CaP motoneuron Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

tardbp

Danio rerio

Structure: CaP motoneuron

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HDAC6 interactions

Biological Process

negative regulation of protein phosphorylation
transcription by RNA polymerase II
mRNA processing
RNA splicing
negative regulation of gene expression

Molecular Function

double-stranded DNA binding
DNA-binding transcription factor activity
RNA binding
single-stranded RNA binding
mRNA 3'-UTR binding

Cellular Component

nucleus
nucleoplasm
perichromatin fibrils
cytoplasm
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240185
Coding exons: 5
Length: 13383
Individuals with no LoFs: 125746
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125748
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	74	234	0.317	0.0000129	2753
Missense (PolyPhen)		3	39.151	0.076627		553
Synonymous	-0.752	97	88.0	1.10	0.00000561	790
Loss of Function	3.62	1	17.2	0.0581	9.23e-7	194

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)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA and RNA-binding protein which regulates transcription and splicing. Involved in the regulation of CFTR splicing. It promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3'-splice site of this exon. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis. May also be involved in microRNA biogenesis, apoptosis and cell division. Can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat. Stabilizes the low molecular weight neurofilament (NFL) mRNA through a direct interaction with the 3' UTR. {ECO:0000269|PubMed:11285240, ECO:0000269|PubMed:17481916}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 10 (ALS10) [MIM:612069]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:18288693, ECO:0000269|PubMed:18309045, ECO:0000269|PubMed:18372902, ECO:0000269|PubMed:18396105, ECO:0000269|PubMed:18438952, ECO:0000269|PubMed:19224587, ECO:0000269|PubMed:19350673, ECO:0000269|PubMed:19655382, ECO:0000269|PubMed:19695877, ECO:0000269|PubMed:20740007, ECO:0000269|PubMed:21220647, ECO:0000269|PubMed:21418058, ECO:0000269|PubMed:22456481}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.254

Intolerance Scores

RVIS EVS: -0.38
RVIS percentile EVS: 27.42

Essentials

Essential (CRISPR): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.895

Gene Damage Prediction

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