TWNK

protein-coding

twinkle mtDNA helicase, the group of DNA helicases

Gene summary

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]

Previous symbols:

IOSCA
C10orf2

MANE transcript

NM_021830.5

Inheritance

AD, AR

ClinVar variants

P:101U:319B:161

Top phenotype

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Perrault syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr10:100,987,367-100,994,403

External References & Databases

Ensembl (ENSG00000107815)

Transcript & Mutation Effects

hg38 • Region Span ~7.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012241

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012241

Submitter: Labcorp Genetics (formerly Invitae)

Perrault syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014504

Submitter: PanelApp Australia

Perrault syndrome 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014504

Submitter: ClinGen

TWNK was first reported in relation to autosomal recessive Perrault Syndrome in 2005 (Nikali et al., PMID: 16135556). This condition is characterized by childhood-onset, progressive, and moderate-to-profound hearing loss, as well as ocular anomalies (such as nystagmus and ophthalmoplegia); ataxia; hypotonia; neuropathy; seizures; brain structural anomalies (including cerebellar atrophy); demyelination; and, in females, amenorrhea/gonadal dysgenesis. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Perrault Syndrome (OMIM: 616138) and Mitochondrial DNA Depletion Syndrome (OMIM: 271245). However, due to a different inheritance pattern and phenotypic variability the following disease assertion was split from the other two assertions: Progressive External Ophthalmoplegia (OMIM: 606075). The split curation for autosomal dominant Progressive External Ophthalmoplegia will be curated separately. 25 variants (missense, frameshift, nonsense, and splicing) that have been reported in over 20 probands in 11 publications (PMIDs: 16135556, 24102492, 24816431, 25355836, 26920903, 26970254, 27551684, 28178980, 31455392, 32281099, 39780253) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models; gEAR database expression; PMID: 16301523). Mouse models of TWNK missense and duplication mutants indicate that mutants have altered TWNK expression, mitochondrial degradation, and run longer distances in the cage wheel study, compared to the wild-type. Expression level evidence shows strong cochlear expression. In summary, there is definitive evidence supporting the relationship between TWNK and autosomal recessive Perrault Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

mitochondrial DNA depletion syndrome 7 (hepatocerebral type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010060

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 7 (hepatocerebral type)SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010060

Submitter: Orphanet

mitochondrial DNA depletion syndrome, hepatocerebrorenal formSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018197

Submitter: Orphanet

Perrault syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017312

Submitter: Orphanet

autosomal dominant progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008003

Submitter: Orphanet

mitochondrial DNA depletion syndrome 7 (hepatocerebral type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010060

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Perrault syndrome 5AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Biochemical

Rationale: Individuals may have biochemical manifestations, including fasting hypoglycemia responsive to glucose therapy

Refs: 8133312; 7719341; 10522883; 11431692; 12210792; 16135556; 17921179; 17722119; 18775955; 18971204; 20479361; 20880070; 21519523; 21681116; 21689831; 22353293; 22928142; 23375728; 25355836

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TWNK variants in ClinVar

28 Conditions Cataloged

not providedTotal: 548

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3Total: 81

Infantile onset spinocerebellar ataxiaTotal: 70

not specifiedTotal: 45

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesisTotal: 37

Autosomal recessive cerebellar ataxiaTotal: 33

TWNK-related disorderTotal: 31

Perrault syndrome 5Total: 25

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021830.5. 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			12 clinvar	144 clinvar		156
missense	17 clinvar	50 clinvar	302 clinvar	16 clinvar	1 clinvar	386
nonsense	5 clinvar	10 clinvar				15
start loss						0
frameshift	12 clinvar	6 clinvar	4 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	35	66	319	160	1	581

Highest pathogenic variant AF is 0.00011833469

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021830.5	RefSeq	NP_068602.2	5	MANE Select
ENST00000311916.8	Ensembl	ENSP00000309595.2	5	MANE Select
NM_001163812.2	RefSeq	NP_001157284.1	4	Standard
NM_001163813.2	RefSeq	NP_001157285.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitochondrial biogenesis

Biological Process

mitochondrial DNA replication
DNA unwinding involved in DNA replication
mitochondrial transcription
mitochondrion organization
protein hexamerization

Molecular Function

protease binding
single-stranded DNA binding
ATP binding
5'-3' DNA helicase activity

Cellular Component

mitochondrial matrix
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311916
Coding exons: 5
Length: 7035
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.61	301	390	0.771	0.0000268	4423
Missense (PolyPhen)		36	88.758	0.4056		1095
Synonymous	-0.617	166	156	1.06	0.00000928	1464
Loss of Function	3.42	10	30.3	0.330	0.00000258	258

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in mitochondrial DNA (mtDNA) metabolism. Could function as an adenine nucleotide-dependent DNA helicase. Function inferred to be critical for lifetime maintenance of mtDNA integrity. In vitro, forms in combination with POLG, a processive replication machinery, which can use double-stranded DNA (dsDNA) as template to synthesize single-stranded DNA (ssDNA) molecules. May be a key regulator of mtDNA copy number in mammals. {ECO:0000269|PubMed:15167897}.;
Disease: DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: A severe disease associated with mitochondrial dysfunction. Some patients are affected by progressive atrophy of the cerebellum, brain stem, the spinal cord, and sensory axonal neuropathy. Clinical features include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural hearing deficit, sensory axonal neuropathy, epileptic encephalopathy and female hypogonadism. In some individuals liver dysfunction and multi- organ failure is present. {ECO:0000269|PubMed:16135556, ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault syndrome, a sex-influenced disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. {ECO:0000269|PubMed:25355836}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.154

Intolerance Scores

RVIS EVS: -0.78
RVIS percentile EVS: 12.97

Essentials

Essential (gene trap): N