TIA1

protein-coding

TIA1 cytotoxic granule associated RNA binding protein, the group of RNA binding motif containing

Gene summary

The product encoded by this gene is a member of a RNA-binding protein family and possesses nucleolytic activity against cytotoxic lymphocyte (CTL) target cells. It has been suggested that this protein may be involved in the induction of apoptosis as it preferentially recognizes poly(A) homopolymers and induces DNA fragmentation in CTL targets. The major granule-associated species is a 15-kDa protein that is thought to be derived from the carboxyl terminus of the 40-kDa product by proteolytic processing. Alternative splicing resulting in different isoforms has been found for this gene. [provided by RefSeq, May 2017]

MANE transcript

NM_022173.4

Inheritance

AD, SD

ClinVar variants

P:2U:147B:64

Top phenotype

Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia; Welander distal myopathy

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr2:70,209,444-70,248,660

External References & Databases

Ensembl (ENSG00000116001)

Transcript & Mutation Effects

hg38 • Region Span ~39.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis 26 with or without frontotemporal dementiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030885

Submitter: Labcorp Genetics (formerly Invitae)

distal myopathy, Welander typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011466

Submitter: Labcorp Genetics (formerly Invitae)

distal myopathy, Welander typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011466

Submitter: Orphanet

amyotrophic lateral sclerosis 26 with or without frontotemporal dementiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030885

Submitter: ClinGen

*TIA1* was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) type 26 with or without FTD in 2017 (Mackenzie et al., PMID: 28817800). *TIA1* is an RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich RNA sequences. It also participates in the cellular response to environmental stress by promoting the recruitment of untranslated mRNAs to cytoplasmic stress granules. *TIA1* has also been associated with autosomal dominant Welander distal myopathy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypic variability and in molecular mechanism. Despite both diseases being caused by missense mutations in the low complexity domain of *TIA1*, Welander distal myopathy is caused by a founder mutation E384K. There have been no reports of patients with this variant developing ALS. Therefore, the following disease entities have been split into separate disease entities, ALS26 with or without FTD (OMIM:619133) and Welander distal myopathy (OMIM:604454). Five missense variants that have been reported in six probands in four publications (PMIDs: 28817800, 29370934, 29699721, 29773329) are included in this curation. Six other reported missense variants have relatively high minor allele frequencies in population databases (>0.00001 in gnomAD) and were not scored as genetic-level evidence (PMIDs: 28817800 and 29886022). This gene-disease relationship is also supported by experimental evidence. *TIA1* is a component of stress granules and since stress granules play a role in ALS, points were given for biochemical function. Expression studies via immunohistochemistry on lumbar spinal cord of a *SOD1*G86S patient revealed an abundance of *TIA1* positive puncta granules in neuronal and non-neuronal cells; in contrast, *TIA1* immunoreactivity was restricted to the nucleus of motor neurons in controls (PMID: 33025330). In vitro experiments show that ALS associated variants, particularly those that affect proline residues, affect stress granule dynamics by decreasing their mobility and delaying their clearance (PMIDs: 28817800, 34310938). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on October 11, 2022 (SOP Version 9).

amyotrophic lateral sclerosis 26 with or without frontotemporal dementiaMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0030885

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia; Welander distal myopathyAD

Manifestation: Musculoskeletal; 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: 23348830; 28817800; 29216908

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TIA1 variants in ClinVar

7 Conditions Cataloged

Welander distal myopathyTotal: 261

not providedTotal: 71

not specifiedTotal: 25

Inborn genetic diseasesTotal: 14

Amyotrophic lateral sclerosis 26 with or without frontotemporal dementiaTotal: 5

TIA1-related disorderTotal: 4

AMYOTROPHIC LATERAL SCLEROSIS 26 WITH FRONTOTEMPORAL DEMENTIATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022173.4. 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			2 clinvar	56 clinvar	3 clinvar	61
missense		2 clinvar	123 clinvar	5 clinvar		130
nonsense			2 clinvar			2
start loss			2 clinvar			2
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	0	2	147	61	3	213

Highest pathogenic variant AF is 0.000021712023

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 116 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022173.4	RefSeq	NP_071505.2	13	MANE Select
ENST00000433529.7	Ensembl	ENSP00000401371.2	13	MANE Select
NM_001351508.2	RefSeq	NP_001338437.1	13	Standard
NM_001351509.2	RefSeq	NP_001338438.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FGFR2 alternative splicing
Signaling by FGFR2
Signal Transduction
Signaling by FGFR
Signaling by Receptor Tyrosine Kinases

Biological Process

apoptotic process
fibroblast growth factor receptor signaling pathway
negative regulation of translation
negative regulation of cytokine biosynthetic process
regulation of mRNA splicing, via spliceosome

Molecular Function

RNA binding
protein binding
poly(A) binding
AU-rich element binding

Cellular Component

nucleoplasm
cytoplasm
cytosol
cytoplasmic stress granule
nuclear stress granule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433529
Coding exons: 13
Length: 39217
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.07	129	214	0.602	0.0000108	2537
Missense (PolyPhen)		20	50.431	0.39658		608
Synonymous	-0.141	70	68.5	1.02	0.00000347	694
Loss of Function	3.87	7	29.8	0.235	0.00000161	306

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	0.000093	0.000046	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in alternative pre-RNA splicing and regulation of mRNA translation by binding to AU-rich elements (AREs) located in mRNA 3' untranslated regions (3' UTRs). Possesses nucleolytic activity against cytotoxic lymphocyte target cells. May be involved in apoptosis.;
Disease: DISEASE: Welander distal myopathy (WDM) [MIM:604454]: An autosomal dominant disorder characterized by adult onset of distal muscle weakness predominantly affecting the distal long extensors of the hands, with slow progression to involve all small hand muscles and the lower legs. Skeletal muscle biopsy shows myopathic changes and prominent rimmed vacuoles. Rare homozygous patients showed earlier onset, faster progression, and proximal muscle involvement. {ECO:0000269|PubMed:23348830, ECO:0000269|PubMed:23401021}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.263

Intolerance Scores

LoFtool: 0.354
RVIS EVS: 0.24
RVIS percentile EVS: 69.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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