Charcot-Marie-Tooth disease axonal type 2U

Summary

Charcot-Marie-Tooth disease axonal type 2U (MONDO:0014566) is a disease caused by MARS1 (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MARS1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 813

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2U
Mondo ID	MONDO:0014566
OMIM	616280
Orphanet	397735
DOID	DOID:0110173
SNOMED CT	765046002
UMLS	C4084821
MedGen	906504
GARD	0017638
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2 due to MARS mutation · autosomal dominant Charcot-Marie-Tooth disease type 2U · Charcot-Marie-Tooth disease type 2 caused by mutation in MARS · Charcot-Marie-Tooth disease, axonal, type 2U · CMT2U · MARS Charcot-Marie-Tooth disease type 2

Data availability: 813 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease type 2 › Charcot-Marie-Tooth disease axonal type 2U

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

342 uncertain significance, 223 likely benign, 16 conflicting classifications of pathogenicity, 11 benign/likely benign, 7 benign, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032278	NM_004990.4(MARS1):c.1294-19C>G	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056553	NM_004990.4(MARS1):c.1792C>T (p.Arg598Cys)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163539	NM_004990.4(MARS1):c.212del (p.Leu71fs)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172763	NM_004990.4(MARS1):c.1793G>A (p.Arg598His)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681687	NM_004990.4(MARS1):c.323A>G (p.Lys108Arg)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681720	NM_004990.4(MARS1):c.1127G>A (p.Arg376Gln)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681736	NM_004990.4(MARS1):c.1422G>C (p.Trp474Cys)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681737	NM_004990.4(MARS1):c.1445C>T (p.Thr482Ile)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681773	NM_004990.4(MARS1):c.2114dup (p.Leu705fs)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1799748	NM_004990.4(MARS1):c.2392-5dup	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1800266	NM_004990.4(MARS1):c.491-5C>G	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242615	NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384378	NM_004990.4(MARS1):c.1540-3C>T	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389593	NM_004990.4(MARS1):c.2391A>C (p.Thr797=)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420243	NM_004990.4(MARS1):c.661G>A (p.Glu221Lys)	MARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196354	NM_002693.3(POLG):c.803G>C (p.Gly268Ala)	POLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1186581	NM_004990.4(MARS1):c.31G>A (p.Gly11Ser)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
120186	NM_004990.4(MARS1):c.13G>A (p.Val5Met)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681667	NM_004990.4(MARS1):c.2T>A (p.Met1Lys)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1681668	NM_004990.4(MARS1):c.67C>G (p.Arg23Gly)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1681672	NM_004990.4(MARS1):c.109+7GTGCTG[3]	ARHGAP9	Uncertain significance	criteria provided, single submitter
1800437	NM_004990.4(MARS1):c.79G>A (p.Glu27Lys)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1939722	NM_004990.4(MARS1):c.5G>C (p.Arg2Thr)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1944205	NM_004990.4(MARS1):c.86T>C (p.Leu29Pro)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1965121	NM_004990.4(MARS1):c.73A>G (p.Arg25Gly)	ARHGAP9	Uncertain significance	criteria provided, single submitter
1980062	NM_004990.4(MARS1):c.109G>A (p.Asp37Asn)	ARHGAP9	Uncertain significance	criteria provided, single submitter
2059873	NM_004990.4(MARS1):c.71G>C (p.Gly24Ala)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2190158	NM_004990.4(MARS1):c.89T>G (p.Ile30Ser)	ARHGAP9	Uncertain significance	criteria provided, single submitter
2925127	NM_004990.4(MARS1):c.31G>C (p.Gly11Arg)	ARHGAP9	Uncertain significance	criteria provided, single submitter
3762779	NM_004990.4(MARS1):c.58G>A (p.Gly20Arg)	ARHGAP9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MARS1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2U	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MARS1	Orphanet:397735	Autosomal dominant Charcot-Marie-Tooth disease type 2U
MARS1	Orphanet:401835	Autosomal recessive spastic paraplegia type 70
MARS1	Orphanet:440427	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
SDR9C7	Orphanet:313	Lamellar ichthyosis
SDR9C7	Orphanet:79394	Congenital ichthyosiform erythroderma
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	gencc,clinvar
ARHGAP9	HGNC:14130	ENSG00000123329	Q9BRR9	Rho GTPase-activating protein 9	clinvar
DCTN2	HGNC:2712	ENSG00000175203	Q13561	Dynactin subunit 2	clinvar
SDR9C7	HGNC:29958	ENSG00000170426	Q8NEX9	Short-chain dehydrogenase/reductase family 9C member 7	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
ARHGAP9	Rho GTPase-activating protein 9	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
DCTN2	Dynactin subunit 2	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
SDR9C7	Short-chain dehydrogenase/reductase family 9C member 7	Plays a crucial role in the formation of the epidermal permeability barrier.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	3.5×	0.530
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C
ARHGAP9	Scaffold/PPI	no		RhoGAP_dom, WW_dom, SH3_domain
DCTN2	Other/Unknown	no		Dynamitin
SDR9C7	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
blood	1
spleen	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
skin of abdomen	1
skin of leg	1
zone of skin	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ARHGAP9	235	broad	marker	granulocyte, blood, spleen
DCTN2	295	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
SDR9C7	113	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS1	5,727
POLG	3,400
DCTN2	2,922
ARHGAP9	1,748
SDR9C7	785

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
MARS1	P56192	7
ARHGAP9	Q9BRR9	3
DCTN2	Q13561	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SDR9C7	Q8NEX9	93.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 5 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	228.4×	0.071	POLG
The canonical retinoid cycle in rods (twilight vision)	1	103.8×	0.071	SDR9C7
Cytosolic tRNA aminoacylation	1	87.8×	0.071	MARS1
tRNA Aminoacylation	1	57.1×	0.071	MARS1
COPI-independent Golgi-to-ER retrograde traffic	1	41.5×	0.071	DCTN2
Selenoamino acid metabolism	1	39.4×	0.071	MARS1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	38.7×	0.071	DCTN2
Transcriptional and post-translational regulation of MITF-M expression and activity	1	35.7×	0.071	MARS1
Loss of Nlp from mitotic centrosomes	1	31.7×	0.071	DCTN2
Loss of proteins required for interphase microtubule organization from the centrosome	1	31.7×	0.071	DCTN2
AURKA Activation by TPX2	1	30.4×	0.071	DCTN2
Recruitment of mitotic centrosome proteins and complexes	1	27.2×	0.071	DCTN2
Regulation of PLK1 Activity at G2/M Transition	1	25.4×	0.071	DCTN2
Recruitment of NuMA to mitotic centrosomes	1	23.3×	0.071	DCTN2
MITF-M-regulated melanocyte development	1	22.8×	0.071	MARS1
Anchoring of the basal body to the plasma membrane	1	22.6×	0.071	DCTN2
COPI-mediated anterograde transport	1	22.0×	0.071	DCTN2
MHC class II antigen presentation	1	17.8×	0.082	DCTN2
RHOA GTPase cycle	1	14.9×	0.091	ARHGAP9
CDC42 GTPase cycle	1	14.5×	0.091	ARHGAP9
Metabolism of amino acids and derivatives	1	13.5×	0.092	MARS1
Translation	1	12.4×	0.093	MARS1
RAC1 GTPase cycle	1	12.2×	0.093	ARHGAP9
Neutrophil degranulation	1	4.6×	0.224	ARHGAP9
Developmental Biology	1	2.9×	0.325	MARS1
Metabolism of proteins	1	2.5×	0.357	MARS1
Metabolism	1	2.3×	0.362	MARS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
methionyl-tRNA aminoacylation	1	1685.2×	0.009	MARS1
DNA replication proofreading	1	1123.5×	0.009	POLG
mitochondrial DNA replication	1	306.4×	0.014	POLG
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	306.4×	0.014	MARS1
base-excision repair, gap-filling	1	224.7×	0.014	POLG
DNA metabolic process	1	210.7×	0.014	POLG
rRNA transcription	1	198.3×	0.014	MARS1
tRNA aminoacylation for protein translation	1	168.5×	0.014	MARS1
melanosome transport	1	153.2×	0.014	DCTN2
protein localization to centrosome	1	134.8×	0.014	DCTN2
cellular response to platelet-derived growth factor stimulus	1	129.6×	0.014	MARS1
DNA-templated DNA replication	1	112.3×	0.015	POLG
retinol metabolic process	1	99.1×	0.015	SDR9C7
base-excision repair	1	93.6×	0.015	POLG
mitotic metaphase chromosome alignment	1	76.6×	0.017	DCTN2
steroid metabolic process	1	67.4×	0.018	SDR9C7
cellular response to epidermal growth factor stimulus	1	63.6×	0.018	MARS1
mitotic spindle organization	1	54.4×	0.020	DCTN2
small GTPase-mediated signal transduction	1	36.6×	0.028	ARHGAP9
regulation of small GTPase mediated signal transduction	1	28.8×	0.034	ARHGAP9

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 4

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4
MARS1	0	0
ARHGAP9	0	0
DCTN2	0	0
SDR9C7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
MARS1	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MARS1	6.1.1.10	methionine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ARHGAP9, DCTN2, SDR9C7

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MARS1	26	—
ARHGAP9	0	—
DCTN2	0	—
SDR9C7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.