TACO1

protein-coding

translational activator of cytochrome c oxidase I, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a mitochondrial protein that function as a translational activator of mitochondrially-encoded cytochrome c oxidase 1. Mutations in this gene are associated with Leigh syndrome.[provided by RefSeq, Mar 2010]

Previous symbols:

CCDC44

MANE transcript

NM_016360.4

Inheritance

ClinVar variants

P:17U:87B:43

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 8

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr17:63,600,882-63,608,365

External References & Databases

Ensembl (ENSG00000136463)

Transcript & Mutation Effects

hg38 • Region Span ~7.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TACO1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. The TACO1 gene encodes the translational activator of cytochrome c oxidase I protein, which is required for translation of the cytochrome c oxidase subunit I, a component of complex IV of the mitochondrial respiratory complex. The TACO1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2009 (PMID: 19503089). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two loss of function variants in this gene have been reported in two consanguineous families in two publications (PMIDs: 19503089, 25044680). Variants in this gene segregated with disease in five additional family members, and segregation evidence was scored for one family (PMID: 19503089). Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by the biochemical function of the protein, functional alteration and rescue experiments in patient fibroblasts, and a homozygous knockout mouse model showed complex IV deficiency and a similar phenotype to human patients (PMIDs: 19503089, 27319982). In summary, there is moderate evidence to support the relationship between TACO1 and Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2019.

mitochondrial complex IV deficiency, nuclear type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033638

Submitter: G2P

mitochondrial complex IV deficiency, nuclear type 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033638

Submitter: Ambry Genetics

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TACO1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. *TACO1* encodes the translational activator of cytochrome c oxidase I protein, which is required for translation of the cytochrome c oxidase subunit I (COX I), a component of complex IV of the mitochondrial respiratory chain. *TACO1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19503089). While various names have been given to the constellation of features seen in those with *TACO1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TACO1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *TACO1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP V6), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the two probands included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four frameshift or termination variants in five probands from four publications (PMIDs: 19503089, 25044680, 32444556, 33709035). Age of onset ranges from childhood to adulthood and all reported cases appear to be living at the time of report. Clinical features include typically childhood onset motor regression, cognitive decline, dystonia, muscle weakness, optic atrophy, and sensorimotor peripheral neuropathy. Muscle biopsies showed complex IV deficiency and COX-negative fibers. Brain imaging was consistent with leukoencephalopathy and/or LSS. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of TACO1, functional alteration in patient cells, rescue in patient cells, and a mouse model (PMIDs: 33709035, 19503089, 27319982). In summary, there is definitive evidence to support the relationship between *TACO1* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 29, 2024 (SOP Version 10).

mitochondrial complex IV deficiency, nuclear type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033638

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex IV deficiency, nuclear type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033638

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 8AR

Manifestation: Biochemical; 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: 19503089

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TACO1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 101

Mitochondrial complex IV deficiency, nuclear type 8Total: 51

Inborn genetic diseasesTotal: 38

Mitochondrial complex IV deficiency, nuclear type 1Total: 16

TACO1-related disorderTotal: 8

not specifiedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016360.4. 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	33 clinvar		36
missense		1 clinvar	83 clinvar	9 clinvar	1 clinvar	94
nonsense	1 clinvar	4 clinvar				5
start loss						0
frameshift	1 clinvar	7 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)		3 clinvar				3
Total	2	15	87	42	1	147

Highest pathogenic variant AF is 0.00003965633

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016360.4	RefSeq	NP_057444.2	5	MANE Select
ENST00000258975.7	Ensembl	ENSP00000258975.6	5	MANE Select
ENST00000684587.1	Ensembl	ENSP00000507435.1	5	Standard
ENST00000921365.1	Ensembl	ENSP00000591424.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport

Biological Process

regulation of translation

Molecular Function

protein binding

Cellular Component

nucleus
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258975
Coding exons: 5
Length: 7495
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.938	133	167	0.796	0.00000868	1927
Missense (PolyPhen)		34	46.98	0.72371		601
Synonymous	-0.570	76	69.9	1.09	0.00000385	612
Loss of Function	1.37	6	10.9	0.552	5.46e-7	138

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a translational activator of mitochondrially- encoded cytochrome c oxidase 1. {ECO:0000269|PubMed:19503089}.;
Disease: DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.240

Intolerance Scores

LoFtool: 0.565
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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