Charcot-Marie-Tooth disease type 1B

Summary

Charcot-Marie-Tooth disease type 1B (MONDO:0007307) is a disease caused by MPZ (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: MPZ (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 124
• Phenotypes (HPO): 14
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000615	Abnormal pupil morphology	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003469	Peripheral dysmyelination	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003712	Skeletal muscle hypertrophy	Frequent (30-79%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 1B
Mondo ID	MONDO:0007307
OMIM	118200
Orphanet	101082
DOID	DOID:0110152
ICD-11	1632280319
NCIT	C118782
UMLS	C0270912
MedGen	124377
GARD	0001246
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 1B · Charcot-Marie-Tooth disease type 1 caused by mutation in MPZ · Charcot-Marie-Tooth disease, demyelinating, type 1B · Charcot-Marie-Tooth disease, type 1B · CMT 1B · CMT1B · HMSN 1B · HMSN IB · HMSN1 · HMSN1B · MPZ Charcot-Marie-Tooth disease type 1

Data availability: 124 ClinVar variants · 3 GenCC gene-disease records · 10 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease dominant intermediate D › Charcot-Marie-Tooth disease type 1B

Related subtypes (2): Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2J

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

124 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 27 conflicting classifications of pathogenicity, 25 pathogenic, 20 pathogenic/likely pathogenic, 13 likely pathogenic, 4 benign/likely benign, 3 not provided, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
208147	NM_000530.6(MPZ):c.[241C>T;337G>T]		Pathogenic	no assertion criteria provided
559476	Single allele		Pathogenic	criteria provided, single submitter
1067479	NM_000530.8(MPZ):c.277G>A (p.Gly93Arg)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14166	NM_000530.8(MPZ):c.286A>G (p.Lys96Glu)	MPZ	Pathogenic	criteria provided, single submitter
14167	NM_000530.8(MPZ):c.270C>A (p.Asp90Glu)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14170	NM_000530.8(MPZ):c.499G>C (p.Gly167Arg)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14171	NM_000530.8(MPZ):c.646-7_647delinsGCAGGAGAG	MPZ	Pathogenic	no assertion criteria provided
14172	NM_000530.8(MPZ):c.404T>C (p.Ile135Thr)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14174	NM_000530.8(MPZ):c.293G>C (p.Arg98Pro)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14175	NM_000530.8(MPZ):c.292C>T (p.Arg98Cys)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14176	NM_000530.8(MPZ):c.293G>A (p.Arg98His)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14177	NM_000530.8(MPZ):c.188C>T (p.Ser63Phe)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14179	NM_000530.8(MPZ):c.242A>G (p.His81Arg)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14181	NM_000530.8(MPZ):c.371C>T (p.Thr124Met)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14184	NM_000530.8(MPZ):c.224A>T (p.Asp75Val)	MPZ	Pathogenic	criteria provided, single submitter
14185	NM_000530.8(MPZ):c.131C>T (p.Ser44Phe)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14186	NM_000530.8(MPZ):c.393C>A (p.Asn131Lys)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14191	NM_000530.8(MPZ):c.434A>C (p.Tyr145Ser)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14200	NM_000530.8(MPZ):c.276G>A (p.Val92=)	MPZ	Pathogenic	criteria provided, single submitter
1685953	NM_000530.8(MPZ):c.401A>T (p.Asp134Val)	MPZ	Pathogenic	criteria provided, single submitter
208146	NM_000530.8(MPZ):c.181G>A (p.Asp61Asn)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
208148	NM_000530.8(MPZ):c.487G>A (p.Gly163Arg)	MPZ	Pathogenic	criteria provided, single submitter
208149	NM_000530.8(MPZ):c.499G>A (p.Gly167Arg)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
208244	NP_000521.1(MPZ):p.Asn116Ser	MPZ	Pathogenic	no assertion criteria provided
217232	NM_000530.8(MPZ):c.116A>C (p.His39Pro)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217233	NM_000530.8(MPZ):c.410G>A (p.Gly137Asp)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243089	NM_000530.8(MPZ):c.403A>C (p.Ile135Leu)	MPZ	Pathogenic	criteria provided, single submitter
246029	NM_000530.8(MPZ):c.584+2T>G	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
246121	NM_000530.8(MPZ):c.188_190del (p.Ser63del)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
246122	NM_000530.8(MPZ):c.129_136del (p.Ser44fs)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 9 · 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
MPZ	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPZ	Orphanet:100046	Autosomal dominant intermediate Charcot-Marie-Tooth disease type D
MPZ	Orphanet:101082	Charcot-Marie-Tooth disease type 1B
MPZ	Orphanet:3115	Roussy-Lévy syndrome
MPZ	Orphanet:324585	Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
MPZ	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
MPZ	Orphanet:64748	Dejerine-Sottas syndrome
MPZ	Orphanet:99942	Autosomal dominant Charcot-Marie-Tooth disease type 2I
MPZ	Orphanet:99943	Autosomal dominant Charcot-Marie-Tooth disease type 2J
SH3TC2	Orphanet:99949	Charcot-Marie-Tooth disease type 4C

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
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	gencc,clinvar
SH3TC2	HGNC:29427	ENSG00000169247	Q8TF17	SH3 domain and tetratricopeptide repeat-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPZ	Myelin protein P0	Is an adhesion molecule necessary for normal myelination in the peripheral nervous system.
SH3TC2	SH3 domain and tetratricopeptide repeat-containing protein 2	Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPZ	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_dom
SH3TC2	Scaffold/PPI	no		SH3_domain, TPR-like_helical_dom_sf, TPR_rpt

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
sural nerve	2
olfactory bulb	1
tibial nerve	1
C1 segment of cervical spinal cord	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SH3TC2	569
MPZ	25

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MPZ	P25189	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH3TC2	Q8TF17	78.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.008	MPZ
Nervous system development	1	42.9×	0.035	MPZ
Developmental Biology	1	14.5×	0.069	MPZ

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
regulation of ERBB signaling pathway	1	8426.0×	9e-04	SH3TC2
cell aggregation	1	4213.0×	9e-04	MPZ
regulation of intracellular protein transport	1	1404.3×	0.002	SH3TC2
regulation of endocytic recycling	1	842.6×	0.002	SH3TC2
peripheral nervous system myelin maintenance	1	766.0×	0.002	SH3TC2
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	561.7×	0.002	MPZ
myelination	1	125.8×	0.009	MPZ
chemical synaptic transmission	1	38.6×	0.026	MPZ

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
MPZ	0	0
SH3TC2	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	1	MPZ
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SH3TC2

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)
MPZ	0	—
SH3TC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study