TIMM8A

protein-coding

translocase of inner mitochondrial membrane 8A

Gene summary

This translocase is involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in Mohr-Tranebjaerg syndrome/Deafness Dystonia Syndrome (MTS/DDS) and it is postulated that MTS/DDS is a mitochondrial disease caused by a defective mitochondrial protein import system. Defects in this gene also cause Jensen syndrome; an X-linked disease with opticoacoustic nerve atrophy and muscle weakness. This protein, along with TIMM13, forms a 70 kDa heterohexamer. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Mar 2009]

Previous symbols:

DFN1

MANE transcript

NM_004085.4

Inheritance

ClinVar variants

P:25U:19B:22

Top phenotype

Opticoacoustic nerve atrophy with dementia; Jensen syndrome; Mohr-Tranebjaerg syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:101,345,661-101,348,742

External References & Databases

Ensembl (ENSG00000126953)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

deafness dystonia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: G2P

deafness dystonia syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: Orphanet

deafness dystonia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: Ambry Genetics

deafness dystonia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: PanelApp Australia

deafness dystonia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: Labcorp Genetics (formerly Invitae)

deafness dystonia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: Genomics England PanelApp

deafness dystonia syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010578

Submitter: ClinGen

The TIMM8A gene has been associated with X-linked deafness dystonia syndrome (aka Mohr-Tranebjærg syndrome) using the ClinGen Clinical Validity Framework as of 8/18/2017. This association was made using case-level data and experimental data. At least 6 probands in 5 publications with at least 8 unique variants (missense, nonsense, frameshift) have been reported in humans, and variants in this gene segregated with disease in 17 additional family members (PMIDs 11803487, 22736418, 18952432, 17999202). TIMM8A was first associated with this disease in humans in 2000 (Tranebjaerg et al.). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is X-linked LOF. This gene-disease association is supported by functional alteration studies in isolated patient cells as well as non patient cells and expression studies (PMIDs: 11956200, 15254020). In summary, TIMM8A is definitively associated with X-linked deafness dystonia 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 ClinGen Hearing Loss Working Group on 12/19/2017.

Clinical Genomic Database (CGD)

Opticoacoustic nerve atrophy with dementia; Jensen syndrome; Mohr-Tranebjaerg syndromeXL

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Pharmacogenomic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Aminoglycosides should be avoided

Comments: Deafness may be postlingual in many individuals with certain TIMM8A-related conditions

Refs: 5649; 7643352; 8841189; 10878669; 11803487; 11405816; 18952432

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TIMM8A variants in ClinVar

6 Conditions Cataloged

not providedTotal: 43

Deafness dystonia syndromeTotal: 23

not specifiedTotal: 18

Inborn genetic diseasesTotal: 5

TIMM8A-related conditionTotal: 3

Auditory neuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004085.4. 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			1 clinvar	19 clinvar		20
missense		2 clinvar	16 clinvar	3 clinvar		21
nonsense	7 clinvar	1 clinvar	1 clinvar			9
start loss						0
frameshift	10 clinvar	1 clinvar				11
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	1 clinvar			5
Total	20	5	19	22	0	66

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004085.4	RefSeq	NP_004076.1	2	MANE Select
ENST00000372902.4	Ensembl	ENSP00000361993.3	2	MANE Select
NM_001145951.2	RefSeq	NP_001139423.1	2	Standard
ENST00000644112.2	Ensembl	ENSP00000494385.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

nervous system development
chaperone-mediated protein transport

Molecular Function

protein binding
metal ion binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372902
Coding exons: 2
Length: 3536
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	17	36.6	0.465	0.00000274	644
Missense (PolyPhen)		0	5.3661	0		125
Synonymous	-0.643	17	13.9	1.22	0.00000100	181
Loss of Function	1.71	0	3.41	0.00	2.74e-7	44

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. Probably necessary for normal neurologic development. {ECO:0000269|PubMed:11489896, ECO:0000269|PubMed:15254020}.;
Disease: DISEASE: Mohr-Tranebjaerg syndrome (MTS) [MIM:304700]: An X-linked recessive disorder characterized by postlingual sensorineural deafness with onset in early childhood, dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. {ECO:0000269|PubMed:10878669, ECO:0000269|PubMed:11803487, ECO:0000269|PubMed:11875042, ECO:0000269|PubMed:11956200}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.250

Intolerance Scores

RVIS EVS: 0.04
RVIS percentile EVS: 56.25

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961