severe early-onset axonal neuropathy due to MFN2 deficiency

Summary

severe early-onset axonal neuropathy due to MFN2 deficiency (MONDO:0019549) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	severe early-onset axonal neuropathy due to MFN2 deficiency
Mondo ID	MONDO:0019549
Orphanet	90118
SNOMED CT	766977007
UMLS	C4707897
MedGen	1641956
GARD	0019123
Is cancer (heuristic)	no

Also known as: AR-CMT2, Ouvrier type · autosomal recessive Charcot-Marie-Tooth disease, Ouvrier type · SEOAN due to MFN2 deficiency

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

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 › hereditary motor and sensory neuropathy › severe early-onset axonal neuropathy due to MFN2 deficiency

Related subtypes (7): polyneuropathy-hand defect syndrome, hereditary thermosensitive neuropathy, autosomal dominant slowed nerve conduction velocity, hereditary sensorimotor neuropathy with hyperelastic skin, demyelinating hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy with acrodystrophy, hereditary motor and sensory neuropathy type 6

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699942	NM_014874.4(MFN2):c.1069A>G (p.Lys357Glu)	MFN2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
MFN2	Definitive	Semidominant	axonal hereditary motor and sensory neuropathy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Miro GTPase Cycle	1	2284.0×	0.003	MFN2
RHOT2 GTPase cycle	1	1631.4×	0.003	MFN2
Mitophagy	1	1038.2×	0.004	MFN2
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.008	MFN2
Selective autophagy	1	278.5×	0.008	MFN2
Autophagy	1	148.3×	0.012	MFN2
Macroautophagy	1	115.3×	0.014	MFN2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.021	MFN2
Hemostasis	1	36.0×	0.033	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	MFN2
Signal Transduction	1	10.2×	0.098	MFN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
type 2 mitophagy	1	3370.4×	0.002	MFN2
mitochondrial membrane organization	1	2407.4×	0.002	MFN2
positive regulation of vascular associated smooth muscle cell apoptotic process	1	2106.5×	0.002	MFN2
mitochondrion localization	1	1685.2×	0.002	MFN2
protein localization to phagophore assembly site	1	991.3×	0.003	MFN2
mitochondrial fusion	1	842.6×	0.003	MFN2
blastocyst formation	1	766.0×	0.003	MFN2
camera-type eye morphogenesis	1	766.0×	0.003	MFN2
negative regulation of Ras protein signal transduction	1	674.1×	0.003	MFN2
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	MFN2
obsolete protein targeting to mitochondrion	1	581.1×	0.003	MFN2
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.003	MFN2
response to unfolded protein	1	300.9×	0.004	MFN2
aerobic respiration	1	247.8×	0.005	MFN2
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	MFN2
apoptotic process	1	28.7×	0.035	MFN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MFN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MFN2	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	MFN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MFN2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.