Charcot-Marie-Tooth disease type 5

Summary

Charcot-Marie-Tooth disease type 5 (MONDO:0010877) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 5
Mondo ID	MONDO:0010877
OMIM	600361
Orphanet	64751
DOID	DOID:0080067
SNOMED CT	76043009
UMLS	C4721916
MedGen	1648461
GARD	0009208
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease-pyramidal features syndrome · hereditary motor and sensory neuropathy 5 · hereditary motor and sensory neuropathy type 5 · HMSN 5 · HMSN5

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › motor peripheral neuropathy › Charcot-Marie-Tooth disease type 5

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, neuropathy, hereditary motor and sensory, type 6A, hereditary motor and sensory neuropathy, Okinawa type, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease axonal type 2C, neuropathy, hereditary motor and sensory, type 6B, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

4 retrieved; paginated sample, class counts are floors:

2 likely benign, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2911947	NM_001376.5(DYNC1H1):c.13763C>T (p.Thr4588Met)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694849	NM_001376.5(DYNC1H1):c.7979T>G (p.Val2660Gly)	DYNC1H1	Likely benign	criteria provided, single submitter
694994	NM_002047.4(GARS1):c.1809+10_1809+12del	GARS1	Likely benign	criteria provided, single submitter
215547	NM_181882.3(PRX):c.4059GGA[6] (p.Glu1361del)	PRX	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
GARS1	Glycine–tRNA ligase	Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP).

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	2	6.0×	0.112
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory bulb	1
sural nerve	1
trigeminal ganglion	1
corpus epididymis	1
gastrocnemius	1
mucosa of stomach	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
cartilage tissue	1
lateral nuclear group of thalamus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
PRDX6	4,106
GARS1	2,426
PRX	1,569

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
GARS1	P41250	14
PRDX6	P30041	3
PRX	Q9BXM0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial tRNA aminoacylation	1	129.8×	0.051	GARS1
Cytosolic tRNA aminoacylation	1	109.8×	0.051	GARS1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	92.1×	0.051	PRX
Detoxification of Reactive Oxygen Species	1	75.1×	0.051	PRDX6
Aggrephagy	1	62.1×	0.051	DYNC1H1
COPI-independent Golgi-to-ER retrograde traffic	1	51.9×	0.051	DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	48.4×	0.051	DYNC1H1
Loss of Nlp from mitotic centrosomes	1	39.6×	0.051	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	39.6×	0.051	DYNC1H1
AURKA Activation by TPX2	1	38.1×	0.051	DYNC1H1
Recruitment of mitotic centrosome proteins and complexes	1	34.0×	0.051	DYNC1H1
Regulation of PLK1 Activity at G2/M Transition	1	31.7×	0.051	DYNC1H1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	29.1×	0.051	DYNC1H1
Recruitment of NuMA to mitotic centrosomes	1	29.1×	0.051	DYNC1H1
Anchoring of the basal body to the plasma membrane	1	28.3×	0.051	DYNC1H1
COPI-mediated anterograde transport	1	27.4×	0.051	DYNC1H1
Neutrophil degranulation	2	11.5×	0.051	PRDX6, DYNC1H1
EML4 and NUDC in mitotic spindle formation	1	23.2×	0.055	DYNC1H1
MHC class II antigen presentation	1	22.3×	0.055	DYNC1H1
Resolution of Sister Chromatid Cohesion	1	21.6×	0.055	DYNC1H1
HCMV Early Events	1	20.2×	0.055	DYNC1H1
RHO GTPases Activate Formins	1	19.4×	0.055	DYNC1H1
Mitotic Prometaphase	1	17.3×	0.059	DYNC1H1
Separation of Sister Chromatids	1	15.2×	0.064	DYNC1H1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial glycyl-tRNA aminoacylation	1	2106.5×	0.007	GARS1
diadenosine tetraphosphate biosynthetic process	1	1404.3×	0.007	GARS1
regulation of metaphase plate congression	1	842.6×	0.007	DYNC1H1
axon ensheathment	1	702.2×	0.007	PRX
establishment of spindle localization	1	702.2×	0.007	DYNC1H1
positive regulation of spindle assembly	1	526.6×	0.007	DYNC1H1
cellular oxidant detoxification	1	468.1×	0.007	PRDX6
positive regulation of intracellular transport	1	421.3×	0.007	DYNC1H1
retrograde axonal transport	1	383.0×	0.007	DYNC1H1
peripheral nervous system myelin maintenance	1	383.0×	0.007	PRX
P-body assembly	1	263.3×	0.008	DYNC1H1
glycerophospholipid catabolic process	1	263.3×	0.008	PRDX6
tRNA aminoacylation for protein translation	1	210.7×	0.008	GARS1
regulation of mitotic spindle organization	1	210.7×	0.008	DYNC1H1
nuclear migration	1	183.2×	0.009	DYNC1H1
hydrogen peroxide catabolic process	1	168.5×	0.009	PRDX6
stress granule assembly	1	150.5×	0.010	DYNC1H1
positive regulation of mRNA splicing, via spliceosome	1	135.9×	0.010	PRDX6
cytoplasmic microtubule organization	1	86.0×	0.014	DYNC1H1
cell redox homeostasis	1	86.0×	0.014	PRDX6
mitotic spindle organization	1	68.0×	0.017	DYNC1H1
regulation of RNA splicing	1	54.7×	0.021	PRX
positive regulation of cold-induced thermogenesis	1	40.9×	0.026	DYNC1H1
response to oxidative stress	1	32.7×	0.032	PRDX6
cell division	1	11.5×	0.084	DYNC1H1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYNC1H1	1	2
GARS1	1	3
PRX	0	0
PRDX6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	GARS1
MOLIBRESIB	2	DYNC1H1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PRDX6	15	Binding:15
GARS1	8	Binding:8
DYNC1H1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2
GARS1	6.1.1.14	glycine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
CRENOLANIB	3	GARS1
MOLIBRESIB	2	DYNC1H1

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	2	DYNC1H1, GARS1
C	Druggable family + PDB, no drug	1	PRDX6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PRX

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)
PRX	0	—
PRDX6	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.