Charcot-Marie-Tooth disease, axonal, type 2EE

Summary

Charcot-Marie-Tooth disease, axonal, type 2EE (MONDO:0032728) is a disease caused by MPV17 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MPV17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, axonal, type 2EE
Mondo ID	MONDO:0032728
OMIM	618400
DOID	DOID:0111559
UMLS	C5193076
MedGen	1677426
GARD	0025730
Is cancer (heuristic)	no

Also known as: CMT2EE

Data availability: 63 ClinVar variants · 2 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 2EE

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 2U, 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, 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

63 retrieved; paginated sample, class counts are floors:

22 pathogenic/likely pathogenic, 19 likely pathogenic, 8 uncertain significance, 7 conflicting classifications of pathogenicity, 5 pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
964822	NM_002437.5(MPV17):c.22C>T (p.Gln8Ter)	LOC129933372	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065949	NM_002437.5(MPV17):c.428T>G (p.Leu143Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071647	NM_002437.5(MPV17):c.139del (p.Gln47fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339934	NM_002437.5(MPV17):c.405C>G (p.Tyr135Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420339	NM_002437.5(MPV17):c.391del (p.Ile132fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451738	NM_002437.5(MPV17):c.405C>A (p.Tyr135Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16160	NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16162	NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16164	NM_002437.5(MPV17):c.359G>A (p.Trp120Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2013271	NM_002437.5(MPV17):c.103C>T (p.Gln35Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214662	NM_002437.5(MPV17):c.135del (p.Glu45fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214664	NM_002437.5(MPV17):c.370C>T (p.Gln124Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203027	NM_002437.5(MPV17):c.461+1G>C	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
2676672	NM_002437.5(MPV17):c.408T>A (p.Tyr136Ter)	MPV17	Pathogenic	criteria provided, single submitter
2676675	NM_002437.5(MPV17):c.354dup (p.Asn119fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676676	NM_002437.5(MPV17):c.101C>G (p.Ser34Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290443	NM_002437.5(MPV17):c.280-1dup	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
381523	NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38347	NM_002437.5(MPV17):c.186+2T>C	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38348	NM_002437.5(MPV17):c.206G>A (p.Trp69Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38352	NM_002437.5(MPV17):c.260AGA[1] (p.Lys88del)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38355	NM_002437.5(MPV17):c.293C>T (p.Pro98Leu)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38356	NM_002437.5(MPV17):c.451dup (p.Leu151fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522375	NM_002437.5(MPV17):c.376-2A>C	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
598353	NM_002437.5(MPV17):c.461+2T>C	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626263	NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
939232	NM_002437.5(MPV17):c.179del (p.Gly60fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2681195	NM_002437.5(MPV17):c.[122G>A];[71-2A>G]		Likely pathogenic	criteria provided, single submitter
1469178	NM_002437.5(MPV17):c.375+2T>C	MPV17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1480456	NM_002437.5(MPV17):c.71-1G>T	MPV17	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
MPV17	Strong	Autosomal recessive	Charcot-Marie-Tooth disease, axonal, type 2EE	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPV17	Orphanet:255229	Navajo neurohepatopathy
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MPV17	HGNC:7224	ENSG00000115204	P39210	Mitochondrial inner membrane protein Mpv17	gencc,clinvar
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPV17	Mitochondrial inner membrane protein Mpv17	Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis.
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPV17	Other/Unknown	no		Mpv17_PMP22
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
dorsal root ganglion	1
lateral nuclear group of thalamus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPV17	283	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEFL	4,644
MPV17	1,251

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPV17	P39210	90.23
NEFL	P07196	73.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ras activation upon Ca2+ influx through NMDA receptor	1	285.5×	0.008	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	271.9×	0.008	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	271.9×	0.008	NEFL
Long-term potentiation	1	237.9×	0.008	NEFL
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.013	NEFL
Protein localization	1	95.2×	0.013	MPV17
Peroxisomal protein import	1	86.5×	0.013	MPV17
RAF/MAP kinase cascade	1	30.5×	0.032	NEFL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament polymerization or depolymerization	1	8426.0×	0.002	NEFL
regulation of mitochondrial DNA metabolic process	1	4213.0×	0.002	MPV17
response to sodium arsenite	1	4213.0×	0.002	NEFL
response to acrylamide	1	4213.0×	0.002	NEFL
neurofilament bundle assembly	1	2808.7×	0.002	NEFL
regulation of axon diameter	1	1685.2×	0.003	NEFL
peripheral nervous system axon regeneration	1	1053.2×	0.003	NEFL
neurofilament cytoskeleton organization	1	842.6×	0.003	NEFL
retrograde axonal transport	1	766.0×	0.003	NEFL
glomerular basement membrane development	1	766.0×	0.003	MPV17
locomotion	1	766.0×	0.003	NEFL
negative regulation of motor neuron apoptotic process	1	766.0×	0.003	NEFL
axonal transport of mitochondrion	1	702.2×	0.003	NEFL
response to corticosterone	1	561.7×	0.004	NEFL
motor neuron apoptotic process	1	561.7×	0.004	NEFL
protein polymerization	1	495.6×	0.004	NEFL
regulation of synapse maturation	1	468.1×	0.004	NEFL
postsynaptic modulation of chemical synaptic transmission	1	337.0×	0.005	NEFL
anterograde axonal transport	1	290.6×	0.005	NEFL
positive regulation of axonogenesis	1	290.6×	0.005	NEFL
spinal cord development	1	255.3×	0.006	NEFL
response to peptide hormone	1	195.9×	0.007	NEFL
inner ear development	1	187.2×	0.007	MPV17
neuromuscular process controlling balance	1	165.2×	0.008	NEFL
intermediate filament organization	1	120.4×	0.010	NEFL
hippocampus development	1	115.4×	0.010	NEFL
response to toxic substance	1	105.3×	0.010	NEFL
cerebral cortex development	1	102.8×	0.010	NEFL
axonogenesis	1	80.2×	0.013	NEFL
microtubule cytoskeleton organization	1	60.6×	0.016	NEFL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPV17	0	0
NEFL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MPV17, NEFL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MPV17	0	—
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.