• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TIMM8A (HGNC:11817) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
translocase of inner mitochondrial membrane 8A
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
DFN1
Alias symbols
DDP, MTS
%HI
16.93(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.65(Read more about gnomAD pLI score)
LOEUF
0.87(Read more about gnomAD LOEUF score)
Cytoband
Xq22.1
Genomic Coordinates
GRCh37/hg19: chrX:100600649-100603730 NCBI Ensembl UCSC
GRCh38/hg38: chrX:101345661-101348742 NCBI Ensembl UCSC
MANE Select Transcript
NM_004085.4 ENST00000372902.4 (Read more about MANE Select)
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 med... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-25240
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Assoc. with Reduced Penetrance:
No
Last Evaluated:
03/24/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 11405816
    Ujike et al (2001) identified a nonsense variant of TIMM8A in a family with multiple affected males with X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome; MTS).
  • PUBMED: 17471106
    Bahmad Jr. et al (2007) reported a frameshift variant in TIMM8A in 16 affected males from a large, multigeneration, Norwegian family with MTS.
  • PUBMED: 22736418
    Ha et al (2012) reported six MTS patients from three Australian families. The affected members had exon 2 deletion (Family A), a single base pair deletion resulting in frameshift (Family B), and a nonsense variant (Family 3) of TIMM8A.
  • PUBMED: 17851739
    Sediva et al (2007) reported several male patients with contiguous X-chromosome deletions encompassing the BTK and TIMM8A genes, resulting in the combination of X-linked agammaglobulinemia (XLA) (associated with loss of the BTK gene) and with sensorineural deafness.
  • PUBMED: 30634948
    Wang et al (2019) identified a novel frameshift variant (p.Leu78SerfsX21) of TIMM8A in a Chinese family with auditory neuropathy using next generation sequencing. In addition, another patient had an inframe variant (c.133_135delGAG). The third patient showed a deletion involving TIMM8A and BTK genes.
  • PUBMED: 31903733
    Neighbors et al (2020) reported a novel TIMM8A variant in a patient with MTS (also called deafness-dystonia-optic neuronopathy (DDON) syndrome) that alters the initiation codon (c.1A>T, p.Met1Leu). Functional analysis showed that this variant resulted in no detectable protein and a reduction in TIMM8A transcript abundance. Mother was found to be a carrier, with low copy numbers of the variant compared to wild type, suggesting that mother may be a mosaic for this variant.
HI Evidence Comments:
The rare, X-linked recessive neurodegenerative disorder, Mohr–Tranebjaerg syndrome (also called deafness-dystonia-optic neuronopathy [DDON] syndrome), is caused by loss-of-function variants or a contiguous gene deletion of Xp22.1 involving DDP1/TIMM8A gene. Frameshifts or premature stops represent the majority of variants in TIMM8A; however, missense variants have also been reported that result in loss of the TIMM8A gene product. Further, contiguous X-chromosome deletions, encompassing the BTK and TIMM8A genes, are associated with the combination of immunodeficiency and sensorineural deafness. The DDP1 protein is located in the intermembrane space of human mitochondria.TIMM8A comprises only two exons, and is involved in the transport and sorting of proteins to the mitochondrial inner membrane. It appears unlikely that pseudogene TIMM8AP1 will interfere with the analysis of TIMM8A. DDON syndrome is characterized by dystonia, early-onset deafness, and various other neurological manifestations. Males are always affected and female carriers may have mild hearing loss and mild dystonia symptoms. Affected males have sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. Females may have mild hearing impairment and focal dystonia (https://www.ncbi.nlm.nih.gov/books/NBK1216/).
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
Triplosensitivity of the DDP1/TIMM8A has not yet been established.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)