TWNK

Summary

TWNK (twinkle mtDNA helicase, HGNC:1160) is a protein-coding gene on chromosome 10q24.31, encoding Twinkle mtDNA helicase (Q96RR1). Mitochondrial helicase involved in mtDNA replication and repair. It is a selective cancer dependency (DepMap: 44.0% of cell lines).

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.

Source: NCBI Gene 56652 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Perrault syndrome 5 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 672 total — 36 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 181
• Cancer dependency (DepMap): dependent in 44.0% of screened cell lines
• MANE Select transcript: NM_021830

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1160
Approved symbol	TWNK
Name	twinkle mtDNA helicase
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	PEO, PEO1, TWINKLE, FLJ21832, TWINL
Ensembl gene	ENSG00000107815
Ensembl biotype	protein_coding
OMIM	606075
Entrez	56652

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000311916, ENST00000370228, ENST00000459764, ENST00000473656, ENST00000476766, ENST00000643860, ENST00000646226, ENST00000647109, ENST00000650396

RefSeq mRNA: 5 — MANE Select: NM_021830 NM_001163812, NM_001163813, NM_001163814, NM_001368275, NM_021830

CCDS: CCDS53570, CCDS7506, CCDS86136, CCDS86137

Canonical transcript exons

ENST00000311916 — 5 exons

Exon	Start	End
ENSE00003465221	100989644	100989884
ENSE00003644429	100990869	100991010
ENSE00003652973	100993190	100994403
ENSE00003658814	100990436	100990543
ENSE00003849932	100987543	100989453

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 83.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2566 / max 136.6362, expressed in 1733 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106620	12.2566	1733

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.18	gold quality
tendon of biceps brachii	UBERON:0008188	83.05	gold quality
gastrocnemius	UBERON:0001388	82.81	gold quality
ventricular zone	UBERON:0003053	82.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.06	gold quality
ganglionic eminence	UBERON:0004023	82.01	gold quality
muscle of leg	UBERON:0001383	81.79	gold quality
gluteal muscle	UBERON:0002000	81.19	silver quality
cortical plate	UBERON:0005343	80.46	gold quality
muscle organ	UBERON:0001630	79.21	gold quality
skeletal muscle organ	UBERON:0014892	79.21	gold quality
left adrenal gland	UBERON:0001234	79.20	gold quality
left adrenal gland cortex	UBERON:0035825	79.17	gold quality
mucosa of transverse colon	UBERON:0004991	79.09	gold quality
right adrenal gland	UBERON:0001233	79.01	gold quality
right adrenal gland cortex	UBERON:0035827	78.99	gold quality
stromal cell of endometrium	CL:0002255	78.88	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.59	gold quality
apex of heart	UBERON:0002098	78.58	gold quality
islet of Langerhans	UBERON:0000006	78.35	gold quality
granulocyte	CL:0000094	78.24	gold quality
adrenal cortex	UBERON:0001235	78.18	gold quality
adrenal gland	UBERON:0002369	78.07	gold quality
right testis	UBERON:0004534	77.87	gold quality
left testis	UBERON:0004533	77.53	gold quality
pancreas	UBERON:0001264	77.01	gold quality
testis	UBERON:0000473	76.90	gold quality
esophagus mucosa	UBERON:0002469	76.74	gold quality
body of pancreas	UBERON:0001150	76.72	gold quality
middle temporal gyrus	UBERON:0002771	76.49	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, FOXC1

miRNA regulators (miRDB)

41 targeting TWNK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-484	98.16	66.92	1074

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 44.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Twinkle appears to be the most common gene associated with adPEO in Australian families. (PMID:12163192)
• both the mitochondrial transcription factor TFAM and mitochondrial single-stranded DNA-binding protein colocalize with Twinkle in intramitochondrial foci (PMID:12686611)
• A novel PEO1 mutation in a sporadic PEO patient with multiple mtDNA deletions. (PMID:12872260)
• mechanism whereby mutations in twinkle result in progressive accumulation of multiple mtDNA deletions in post- mitotic tissues (PMID:15181170)
• A novel heterozygous A to G transition at nucleotide 955 of C10Orf2 (Twinkle)ws found in siblings with sensory ataxic neuropathy. (PMID:15668446)
• the severe neurological phenotype observed in infantile onset spinocerebellar ataxia, suggests that the mutated Twinky and Twinkle play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations [twinky] (PMID:16135556)
• Mitochondrial DNA helicase belongs to the DnaB-like family of replicative DNA helicases. (PMID:17324440)
• Direct sequencing showed a heteroplasmic mutation at nucleotide 7506 in the dihydrouridine stem of the tRNA(Ser(UCN)) gene. (PMID:17614276)
• We report a Spanish family showing a mild phenotype characterized by autosomal dominant ocular myopathy and morphological signs of mitochondrial dysfunction, that harboured a novel(p.R357P) mutation in the hot-spot linker region of the twinkle protein. (PMID:17614277)
• This finding broadens the clinical spectrum of Twinkle gene mutations and further implicates loss of mitochondrial DNA integrity in the pathogenesis of Parkinson disease. (PMID:17620490)
• Identifying other Twinkle mutations in mitochondrial DNA depletion and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on proteins should help in understanding why some mutations are recessive and others are dominant. (PMID:17722119)
• study reports a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement (PMID:17921179)
• The N-terminal part of TWINKLE is required for efficient binding to single-stranded DNA. (PMID:18039713)
• We describe a new de novo mutation (1110C>A) in the PEO1 gene in patients with Ophthalmoplegia, Chronic Progressive External in a mother and her two sons. (PMID:18396044)
• Data show that PEO1 has a major role in determining familial progressive external ophthalmoplegia. (PMID:18575922)
• MtDNA replication pausing is the consequence of Twinkle mutations that predisposes to progressive external ophthalmoplegia. (PMID:18971204)
• A heterozygous mutation predicting a R334Q substitution in Twinkle was associated with progressive external opthalmoplegia and/or Parkinsonism in several members of a family. (PMID:18973250)
• This study widens the mutation spectrum of PEO1 and is the first to report the PEO1 mutation in the Chinese population. (PMID:18989381)
• Association of the T(-365)C POLG1, G(-25)A ANT1 and G(-605)T PEO1 gene polymorphisms with diabetic polyneuropathy in patients with type 1 diabetes mellitus (PMID:19425506)
• heterozygous c.907C>T (p.R303W) mutation found in the N-terminal domain of the human mitochondrial DNA helicase, Twinkle protein, associated with phenotypically mild autosomal dominant progressive external ophthalmoplegia (PMID:19428252)
• Twinkle variations in the linker domain alter cerebral function and further implicate disrupted mitochondrial DNA integrity in the pathogenesis of dementia (PMID:19513767)
• study of a Saudi Arabian family with autosomal dominant progressive external ophthalmoplegia & late onset multi-organ failure caused by a novel PEO1/Twinkle mutation (1078C > G + 1079T > G double nucleotide change predicting a Leu360Gly substitution) (PMID:19853444)
• Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of autosomal dominant progressive external ophthalmoplegia may well be underestimated. (PMID:20479361)
• Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity. (PMID:20659899)
• We present a new French family of whom two members displayed autosomal dominant progressive external ophthalmoplegia associated with the R374Q mutation of the Twinkle gene (PMID:20880070)
• Multimeric unicircular mtDNA molecules are seen in cells expressing Twinkle. (PMID:21540127)
• PEO1 sequencing discloses novel mutations in exons 1 and 4 of the gene in chronic external ophthalmoplegia; this is the first report of a mutation occurring in exon 4. (PMID:21689831)
• A novel homozygous missense mutation c.1366C>G (L456V) in C10orf2 (the Twinkle gene) was identified in a family with infantile onset spinocerebellar ataxia. (PMID:22353293)
• the strand annealing activity of TWINKLE may play a role in recombination-mediated replication initiation found in the mitochondria of mammalian brain and heart or in replication fork regression during repair of damaged DNA replication forks. (PMID:22383523)
• analysis did not reveal disease causing POLG or PEO1 mutations in patients with atypical parkinsonism (PMID:22580846)
• Overexpression of d-mtDNA helicase containing either the K388A or A442P mutations causes a mitochondrial oxidative phosphorylation (OXPHOS) defect that significantly reduces cell proliferation. (PMID:22952820)
• A homozygous mutation in TWINKLE is the cause of multisystemic failure including renal tubulopathy in three consanguinity siblings. (PMID:23375728)
• 16-year follow-up of autosomal dominant progressive external ophthalmoplegia (adPEO) due to the p.R357P gene mutation in PEO1; adPEO due to this mutation is a late-onset ocular myopathy beginning with ptosis and progressing slowly; ophthalmoparesis, if present, is mild (PMID:24018892)
• Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species. (PMID:24218554)
• Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. (PMID:24524965)
• Identified compound heterozygous mutations of the C10orf2 gene as the cause of infantile-onset spinocerebellar ataxia with sensorimotor polyneuropathy and myopathy. (PMID:24816431)
• The mitochondrial replicative helicase Twinkle inefficiently unwinds well characterized intermolecular and intramolecular G-quadruplex DNA substrates, as well as a unimolecular G4 substrate. (PMID:25193669)
• Mutations in Twinkle were linked to Perrault syndrome with neurologic features. (PMID:25355836)
• An electron microscopy model of Twinkle reveals a hexameric two-layered ring comprising the zinc-binding domain and RNA polymerase domain in one layer and the RecA-like hexamerization C-terminal domain in another. (PMID:25824949)
• sequencing coding regions of C10orf2 revealed three variants in three different patients, of which two were novel (c.1964G>A/p.G655D; c.204G>A/p.G68G) variants and one was reported (c.1052A>G/p. N351S). (PMID:26689116)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	twnk	ENSDARG00000099900
mus_musculus	Twnk	ENSMUSG00000025209
rattus_norvegicus	Twnk	ENSRNOG00000014935
drosophila_melanogaster	mtDNA-helicase	FBGN0032154
caenorhabditis_elegans		WBGENE00018514

Protein

Protein identifiers

Twinkle mtDNA helicase — Q96RR1 (reviewed: Q96RR1)

Alternative names: Progressive external ophthalmoplegia 1 protein, T7 gp4-like protein with intramitochondrial nucleoid localization, T7-like mitochondrial DNA helicase, Twinkle protein, mitochondrial

All UniProt accessions (7): Q96RR1, A0A2R8Y4V4, A0A2R8Y746, A0A2R8Y8D3, A0A2R8YF85, A0A3B3IT76, E5KSY5

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial helicase involved in mtDNA replication and repair. Might have a role in mtDNA repair. Has DNA strand separation activity needed to form a processive replication fork for leading strand synthesis which is catalyzed by the formation of a replisome complex with POLG and mtSDB. Preferentially unwinds DNA substrates with pre-existing 5’-and 3’- single-stranded tails but is also active on a 5’- flap substrate. Can dissociate the invading strand of immobile or mobile D-loop DNA structures irrespective of the single strand polarity of the third strand. In addition to its DNA strand separation activity, also has DNA strand annealing, DNA strand-exchange and DNA branch migration activities. Lack DNA unwinding and ATP hydrolysis activities. Does not bind single-stranded or double-stranded DNA.

Subunit / interactions. Interacts with LONP1. Homohexamer (via C-terminus), which assembles in a ring-like structure. Homoheptamer, which assembles in a ring-like structure. Homooctamer, which assembles in a ring-like structure. Oligomers may sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA binding. Oligomerization is Mg(2+), nucleotide and DNA-independent, however, Mg(2+) and nucleotide stabilize the homohexameric form. Interacts with POLG in vitro. Monomer. Does not form oligomers.

Subcellular location. Mitochondrion matrix. Mitochondrion nucleoid. Mitochondrion inner membrane.

Tissue specificity. High relative levels in skeletal muscle, testis and pancreas. Lower levels of expression in the heart, brain, placenta, lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, colon and leukocytes. Expression is coregulated with MRPL43.

Disease relevance. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3 (PEOA3) [MIM:609286] A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. PRLTS5 is an autosomal recessive form characterized by progressive ataxia, axonal neuropathy, hyporeflexia and abnormal eye movements, in addition to deafness and ovarian dysgenesis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strand annealing activity is inhibited by 150 mM NaCl (in vitro).

Domain organisation. N-terminus enhances protein stability and hexamer formation, which is important for DNA binding, and is required for DNA helicase activity and, ultimately, for mtDNA replisome processivity.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96RR1-1	1	yes
Q96RR1-2	2, Twinky
Q96RR1-3	3

RefSeq proteins (5): NP_001157284, NP_001157285, NP_001157286, NP_001355204, NP_068602* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007694	DNA_helicase_DnaB-like_C	Domain
IPR027032	Twinkle-like	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR034154	TOPRIM_DnaG/twinkle	Domain

Pfam: PF13481

Enzyme classification (BRENDA):

• EC 3.6.4.12 — DNA helicase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (60 total): sequence variant 43, region of interest 7, splice variant 3, transit peptide 1, chain 1, compositionally biased region 1, binding site 1, domain 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7T8B	ELECTRON MICROSCOPY	3.8
7T8C	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RR1-F1	78.71	0.49

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 415–422

Mutagenesis-validated functional residues (1):

Position	Phenotype
421	loss of helicase activity on 5’-tailed substrate.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication

MSigDB gene sets: 436 (showing top): REACTOME_DNA_REPLICATION, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GGAANCGGAANY_UNKNOWN, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GARY_CD5_TARGETS_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, HNF1_C, TIEN_INTESTINE_PROBIOTICS_24HR_UP, BONOME_OVARIAN_CANCER_POOR_SURVIVAL_DN, GOBP_DNA_REPLICATION, GOMF_SINGLE_STRANDED_DNA_BINDING, GOCC_NUCLEOID, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (5): DNA-templated DNA replication (GO:0006261), mitochondrial DNA replication (GO:0006264), mitochondrial transcription (GO:0006390), protein hexamerization (GO:0034214), DNA replication (GO:0006260)

GO Molecular Function (13): protease binding (GO:0002020), DNA helicase activity (GO:0003678), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), lipid binding (GO:0008289), ATP hydrolysis activity (GO:0016887), identical protein binding (GO:0042802), 5’-3’ DNA helicase activity (GO:0043139), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), isomerase activity (GO:0016853)

GO Cellular Component (6): mitochondrial chromosome (GO:0000262), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), mitochondrial nucleoid (GO:0042645), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Metabolism of proteins	1
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	5
binding	2
ATP-dependent activity	2
catalytic activity	2
DNA replication	1
DNA-templated DNA replication	1
mitochondrial DNA metabolic process	1
mitochondrial RNA metabolic process	1
DNA-templated transcription	1
mitochondrial gene expression	1
protein complex oligomerization	1
DNA metabolic process	1
DNA biosynthetic process	1
enzyme binding	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
DNA helicase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
chromosome	1
mitochondrial nucleoid	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TWNK	POLG	P54098	996
TWNK	SSBP1	Q04837	996
TWNK	SLC25A4	P12235	921
TWNK	TFAM	Q00059	921
TWNK	POLG2	Q9UHN1	916
TWNK	DGUOK	P78532	896
TWNK	MPV17	P39210	893
TWNK	RRM2B	Q7LG56	880
TWNK	SUCLA2	Q9P2R7	874
TWNK	RNASEH1	O60930	866
TWNK	MGME1	Q9BQP7	856
TWNK	POLRMT	O00411	853
TWNK	DNA2	P51530	843
TWNK	MRPL43	Q8N983	806
TWNK	SLF2	Q8IX21	764

IntAct

82 interactions, top by confidence:

A	B	Type	Score
HEXIM1	CCNT1	psi-mi:“MI:0914”(association)	0.930
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
MECP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
TWNK	LGALS3BP	psi-mi:“MI:0915”(physical association)	0.590
MECP2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ZNF169	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530
RBMX	PTCD1	psi-mi:“MI:0914”(association)	0.530
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
ZNF263	AHCYL1	psi-mi:“MI:0914”(association)	0.530
TWNK	RAD9A	psi-mi:“MI:0914”(association)	0.350
FOXP1	MYL12B	psi-mi:“MI:0914”(association)	0.350
PB2	SEC15L3	psi-mi:“MI:0914”(association)	0.350
ORF73	ECI2	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
HMGB1	SMARCA5	psi-mi:“MI:0914”(association)	0.350
CDX1	ZNF724	psi-mi:“MI:0914”(association)	0.350
TRA2A	GAPDHS	psi-mi:“MI:0914”(association)	0.350
ZNF263	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
PRIMPOL	ECI2	psi-mi:“MI:0914”(association)	0.350
ARHGEF40	ARHGEF11	psi-mi:“MI:0914”(association)	0.350

BioGRID (160): C10orf2 (Affinity Capture-MS), C10orf2 (Affinity Capture-MS), C10orf2 (Affinity Capture-MS), C10orf2 (Affinity Capture-MS), C10orf2 (Co-fractionation), CLTA (Affinity Capture-MS), RAD9A (Affinity Capture-MS), TRIM27 (Affinity Capture-MS), TPM1 (Affinity Capture-MS), B4GALT7 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), DCAF8 (Affinity Capture-MS), C10orf2 (Affinity Capture-MS), EPB41L5 (Affinity Capture-MS), NCOA5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A2AWP8, A2RRH5, C9J798, O43374, O70277, O95294, P04629, P59926, Q0GA42, Q13368, Q14318, Q16512, Q29RM4, Q2HY40, Q2T9P3, Q2TBA3, Q5BIM1, Q5M7W1, Q5R5M3, Q5R811, Q5T7P8, Q5XIS9, Q62746, Q6PFQ7, Q6PFY8, Q7TNM2, Q7TP90, Q7Z4K8, Q8BG60, Q8BHT7, Q8BQC3, Q8C6N3, Q8CIW5, Q8IZ69, Q8NCT1, Q920N2, Q92546, Q925B4

Diamond homologs: Q5ZIW1, Q8CIW5, Q96RR1, Q9VL76

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processing of Capped Intron-Containing Pre-mRNA	7	8.1×	6e-03
Metabolism of RNA	9	5.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

672 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	35
Uncertain significance	343
Likely benign	164
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
162050	NM_021830.5(TWNK):c.1321T>G (p.Trp441Gly)	Pathogenic
1679820	NM_021830.5(TWNK):c.1485-1G>A	Pathogenic
1708153	NM_021830.5(TWNK):c.1729_1732del (p.Ala577fs)	Pathogenic
1998741	NM_021830.5(TWNK):c.517dup (p.Val173fs)	Pathogenic
2109555	NM_021830.5(TWNK):c.16C>T (p.Arg6Ter)	Pathogenic
2123422	NM_021830.5(TWNK):c.1216C>T (p.Arg406Ter)	Pathogenic
2136924	NM_021830.5(TWNK):c.85C>T (p.Arg29Ter)	Pathogenic
214184	NM_021830.5(TWNK):c.1110C>G (p.Phe370Leu)	Pathogenic
214190	NM_021830.5(TWNK):c.1462_1463del (p.Phe488fs)	Pathogenic
225837	NM_021830.5(TWNK):c.333del (p.Leu112fs)	Pathogenic
2694949	NM_021830.5(TWNK):c.1372_1373del (p.Gln458fs)	Pathogenic
2735473	NM_021830.5(TWNK):c.1001G>C (p.Arg334Pro)	Pathogenic
2806473	NM_021830.5(TWNK):c.1325dup (p.Gly442_Ser443insTer)	Pathogenic
3377475	NM_021830.5(TWNK):c.742_745del (p.Phe248fs)	Pathogenic
3648325	NM_021830.5(TWNK):c.699del (p.Ser232_Tyr233insTer)	Pathogenic
3701768	NM_021830.5(TWNK):c.1535_1536del (p.His512fs)	Pathogenic
4085430	NM_021830.5(TWNK):c.961_964del (p.Phe321fs)	Pathogenic
426104	NM_021830.5(TWNK):c.1374G>T (p.Gln458His)	Pathogenic
426105	NM_021830.5(TWNK):c.1391T>C (p.Leu464Pro)	Pathogenic
4277590	NM_021830.5(TWNK):c.1078_1079delinsGG (p.Leu360Gly)	Pathogenic
4616	NM_021830.5(TWNK):c.1054_1092dup (p.His364_Lys365insLeuSerArgIleLeuArgThrAlaLeuProAlaTrpHis)	Pathogenic
4617	NM_021830.5(TWNK):c.1423G>C (p.Ala475Pro)	Pathogenic
4620	NM_021830.5(TWNK):c.944G>T (p.Trp315Leu)	Pathogenic
4621	NM_021830.5(TWNK):c.1061G>C (p.Arg354Pro)	Pathogenic
4622	NM_021830.5(TWNK):c.1142T>C (p.Leu381Pro)	Pathogenic
4624	NM_021830.5(TWNK):c.1106C>A (p.Ser369Tyr)	Pathogenic
4625	NM_021830.5(TWNK):c.955A>G (p.Lys319Glu)	Pathogenic
4626	NM_021830.5(TWNK):c.1370C>T (p.Thr457Ile)	Pathogenic
4630	NM_021830.5(TWNK):c.952G>A (p.Ala318Thr)	Pathogenic
4709763	NM_021830.5(TWNK):c.956A>C (p.Lys319Thr)	Pathogenic

SpliceAI

766 predictions. Top by Δscore:

Variant	Effect	Δscore
10:100989449:CACAG:C	donor_loss	1.0000
10:100989451:CAGGT:C	donor_loss	1.0000
10:100989452:AGGTA:A	donor_loss	1.0000
10:100989453:GGTAA:G	donor_loss	1.0000
10:100989454:G:C	donor_loss	1.0000
10:100989455:T:G	donor_loss	1.0000
10:100989881:TCAGG:T	donor_loss	1.0000
10:100989882:CAGGT:C	donor_loss	1.0000
10:100989883:AGG:A	donor_loss	1.0000
10:100989884:GGT:G	donor_loss	1.0000
10:100989885:G:A	donor_loss	1.0000
10:100989886:T:A	donor_loss	1.0000
10:100990431:CCCA:C	acceptor_loss	1.0000
10:100990432:CCA:C	acceptor_loss	1.0000
10:100990435:G:A	acceptor_loss	1.0000
10:100990435:GGACT:G	acceptor_gain	1.0000
10:100990836:T:TA	acceptor_gain	1.0000
10:100990856:T:TA	acceptor_gain	1.0000
10:100990857:G:A	acceptor_gain	1.0000
10:100990861:T:TA	acceptor_gain	1.0000
10:100990864:CGTA:C	acceptor_loss	1.0000
10:100990865:GTAG:G	acceptor_loss	1.0000
10:100990866:TAGG:T	acceptor_loss	1.0000
10:100990867:A:AG	acceptor_gain	1.0000
10:100990867:A:T	acceptor_loss	1.0000
10:100990867:AG:A	acceptor_gain	1.0000
10:100990868:G:GT	acceptor_gain	1.0000
10:100990868:GG:G	acceptor_gain	1.0000
10:100990868:GGA:G	acceptor_gain	1.0000
10:100990868:GGATC:G	acceptor_gain	1.0000

AlphaMissense

4436 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:100989453:G:A	G415R	1.000
10:100989453:G:C	G415R	1.000
10:100989453:G:T	G415W	1.000
10:100989644:G:A	G415E	1.000
10:100989653:G:A	G418D	1.000
10:100989659:G:A	G420E	1.000
10:100989727:A:C	S443R	1.000
10:100989729:C:A	S443R	1.000
10:100989729:C:G	S443R	1.000
10:100990498:A:C	D516A	1.000
10:100990498:A:T	D516V	1.000
10:100990948:C:G	H558D	1.000
10:100993276:G:C	K607N	1.000
10:100993276:G:T	K607N	1.000
10:100993316:T:C	F621L	1.000
10:100993318:C:A	F621L	1.000
10:100993318:C:G	F621L	1.000
10:100989427:G:C	R406P	0.999
10:100989439:T:C	L410P	0.999
10:100989442:C:A	T411K	0.999
10:100989445:T:A	V412D	0.999
10:100989451:C:A	T414K	0.999
10:100989644:G:T	G415V	0.999
10:100989658:G:A	G420R	0.999
10:100989658:G:C	G420R	0.999
10:100989659:G:T	G420V	0.999
10:100989661:A:C	K421Q	0.999
10:100989662:A:T	K421M	0.999
10:100989676:A:C	S426R	0.999
10:100989678:T:A	S426R	0.999

dbSNP variants (sampled 300 via entrez): RS1000128578 (10:100993112 C>A,T), RS1000237544 (10:100992859 T>C), RS1000469814 (10:100986024 G>T), RS1000734618 (10:100987112 C>A,T), RS1001463681 (10:100986729 A>G), RS1001555971 (10:100993953 G>A), RS1001745445 (10:100985696 A>G,T), RS1001831379 (10:100986972 T>C,G), RS1001889906 (10:100992438 A>G), RS1001920661 (10:100991964 C>T), RS1003768697 (10:100989576 C>T), RS1003774635 (10:100987998 G>C), RS1003924220 (10:100988126 A>C,G), RS1004255982 (10:100991263 T>C), RS1004262960 (10:100990886 A>G)

Disease associations

OMIM: gene MIM:606075 | disease phenotypes: MIM:271245, MIM:303350, MIM:609286, MIM:233400, MIM:616138, MIM:607459, MIM:613832, MIM:213200, MIM:609129, MIM:157640

GenCC curated gene-disease

Disease	Classification	Inheritance
Perrault syndrome 5	Definitive	Autosomal recessive
mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	Strong	Autosomal recessive
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Strong	Autosomal dominant
autosomal dominant progressive external ophthalmoplegia	Supportive	Autosomal dominant
Perrault syndrome	Supportive	Autosomal recessive
mitochondrial DNA depletion syndrome, hepatocerebrorenal form	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Perrault syndrome 5	Definitive	AR

Mondo (15): mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MONDO:0010060), hereditary spastic paraplegia (MONDO:0019064), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (MONDO:0012241), Perrault syndrome (MONDO:0017312), Perrault syndrome 5 (MONDO:0014504), sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (MONDO:0011835), autosomal recessive cerebellar ataxia (MONDO:0015244), third-degree atrioventricular block (MONDO:0000468), mitochondrial disease (MONDO:0044970), auditory neuropathy (MONDO:0021944), depressive disorder (MONDO:0002050), progressive external ophthalmoplegia (MONDO:0005181), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (MONDO:0024528), autosomal dominant progressive external ophthalmoplegia (MONDO:0008003), mitochondrial DNA depletion syndrome, hepatocerebrorenal form (MONDO:0018197)

Orphanet (8): Infantile-onset spinocerebellar ataxia (Orphanet:1186), Hereditary spastic paraplegia (Orphanet:685), Perrault syndrome (Orphanet:2855), Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome (Orphanet:70595), Autosomal recessive cerebellar ataxia (Orphanet:1172), Mitochondrial disease (Orphanet:68380), Progressive external ophthalmoplegia (Orphanet:520820), Progressive myoclonic epilepsy type 5 (Orphanet:402082)

HPO phenotypes

181 total (30 of 181 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000133	Gonadal dysgenesis
HP:0000135	Hypogonadism
HP:0000218	High palate
HP:0000338	Hypomimic face
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000496	Abnormality of eye movement
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000544	External ophthalmoplegia
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0000820	Abnormality of the thyroid gland
HP:0000821	Hypothyroidism

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006921_7	Regular attendance at a pub or social club	1.000000e-08
GCST011878_8	Mitochondrial heteroplasmy measurement	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0600008	mitochondrial heteroplasmy measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D003866	Depressive Disorder	F03.600.300
D017246	Ophthalmoplegia, Chronic Progressive External	C05.651.460.700; C10.292.562.750.250; C10.597.622.447.511; C10.668.491.500.700; C11.590.472.250; C18.452.660.560.700; C23.550.291.500.688; C23.888.592.636.447.511
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C538268	Auditory neuropathy (supp.)
C535523	Infantile onset spinocerebellar ataxia (supp.)
C563575	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 1 (supp.)
C563747	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment, decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D0KG	PUMCi005-A	Induced pluripotent stem cell	Female
CVCL_XM15	HAP1 C10orf2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

172 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04931693	PHASE4	COMPLETED	PECs Block for Pacemaker Insertion in Children
NCT05666219	PHASE4	WITHDRAWN	Reversal of Complete Heart Block With Aminophylline in Inferior Wall Myocardial Infarction Patients
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT02809131	PHASE3	COMPLETED	Perioperative Antibiotic Therapy to Prevent Cardiac Implantable Electronic Device Infections.
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)