TWNK

Chr 10ARAD

twinkle mtDNA helicase

Also known as: ATXN8, C10orf2, IOSCA, MTDPS7, PEO, PEO1, PEOA3, PRLTS5

NCBI Gene: 56652ENSG00000107815UniProt: Q96RR1

This gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is thought to play a key role in mtDNA replication. The protein localizes to the mitochondrial matrix and mitochondrial nucleoids. Mutations in this gene cause infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) and are also associated with several mitochondrial depletion syndromes. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Aug 2009]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)MIM #271245
AR
Perrault syndrome 5MIM #616138
AR
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3MIM #609286
AD
293
ClinVar variants
45
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— TWNK
🧬
Gene-Disease Validity (ClinGen)
Perrault syndrome 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 152 VUS of 293 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.56LOEUF
pLI 0.003
Z-score 3.42
OE 0.33 (0.20–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.61Z-score
OE missense 0.77 (0.70–0.85)
301 obs / 390.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.20–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.70–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 10 / 30.3Missense obs/exp: 301 / 390.4Syn Z: -0.62

ClinVar Variant Classifications

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic24
VUS152
Likely Benign75
Benign4
Conflicting17
21
Pathogenic
24
Likely Pathogenic
152
VUS
75
Likely Benign
4
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
6
10
0
21
Likely Pathogenic
2
16
6
0
24
VUS
2
127
21
2
152
Likely Benign
0
2
13
60
75
Benign
0
1
3
0
4
Conflicting
—17
Total91525362293

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TWNK · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

MIM #271245

Molecular basis of disorder known

Autosomal recessive

Perrault syndrome 5

MIM #616138

Molecular basis of disorder known

Autosomal recessive

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

MIM #609286

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TWNK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mitochondrial DiseasesMitochondrial EncephalomyopathyMitochondrial Encephalopathy

Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

RECRUITING
NCT04802707Phase PHASE2Kenneth Myers, MDStarted 2021-10-18
deoxycytidine and deoxythymidine
Mitochondrial DiseasesBone Remodeling Disorder

The Impact of Mitochondrial Dysfunction on Human Bone Cell Metabolism and Remodelling

ACTIVE NOT RECRUITING
NCT05483738Phase NAAalborg University HospitalStarted 2020-02-01
Clinical assessment, blood samples, bone marrow and bone biopsy

External Resources

Links to major genomics databases and tools