Charcot-Marie-Tooth disease X-linked dominant 1

Summary

Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO:0010549) is a disease caused by GJB1 (GenCC Strong), with 6 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: GJB1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 250
• Phenotypes (HPO): 16

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000763	Sensory neuropathy	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001761	Pes cavus	Very frequent (80-99%)
HP:0007149	Distal upper limb amyotrophy	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0040129	Abnormal nerve conduction velocity	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease X-linked dominant 1
Mondo ID	MONDO:0010549
MeSH	C564446
OMIM	302800, 302900
Orphanet	101075
DOID	DOID:0110209
NCIT	C129068
SNOMED CT	763455008
UMLS	C0393808
MedGen	98290
GARD	0001258
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease X-linked 1 · Charcot-Marie-Tooth disease type X caused by mutation in GJB1 · Charcot-Marie-Tooth disease X-linked dominant 1 · Charcot-Marie-Tooth disease X-linked dominant type 1 · Charcot-Marie-Tooth disease, X-linked dominant, 1 · Charcot-Marie-Tooth disease, X-linked dominant, type 1 · Charcot-Marie-Tooth disease, X-linked, 1 · Charcot-Marie-Tooth neuropathy X type 1 · Charcot-Marie-Tooth neuropathy, X-linked, 1 · Charcot-Marie-Tooth peroneal muscular atrophy and Friedreich ataxia, combined · Charcot-Marie-Tooth peroneal muscular atrophy, X-linked · CMT1X · CMT2 · CMT2, formerly · CMTX · CMTX 1 · CMTX1 · GJB1 Charcot-Marie-Tooth disease type X · hereditary motor and sensory neuropathy, X-linked · HMSN, X-linked (+1 more)

Data availability: 250 ClinVar variants · 3 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › Charcot-Marie-Tooth disease type X › Charcot-Marie-Tooth disease X-linked dominant 1

Related subtypes (5): Charcot-Marie-Tooth disease X-linked dominant 6, Charcot-Marie-Tooth disease X-linked recessive 2, Charcot-Marie-Tooth disease X-linked recessive 3, Charcot-Marie-Tooth disease X-linked recessive 4, Charcot-Marie-Tooth disease X-linked recessive 5

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

250 retrieved; paginated sample, class counts are floors:

88 uncertain significance, 59 pathogenic, 36 likely pathogenic, 31 conflicting classifications of pathogenicity, 28 pathogenic/likely pathogenic, 4 benign/likely benign, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217886	NM_006736.6(DNAJB2):c.352+1G>A	DNAJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1028587	NM_000166.6(GJB1):c.292C>T (p.Gln98Ter)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10431	NM_000166.6(GJB1):c.424C>T (p.Arg142Trp)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10432	NM_000166.6(GJB1):c.514C>T (p.Pro172Ser)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10433	NM_000166.6(GJB1):c.415G>A (p.Val139Met)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10434	NM_000166.6(GJB1):c.397T>C (p.Trp133Arg)	GJB1	Pathogenic	no assertion criteria provided
10435	NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10436	NM_000166.6(GJB1):c.89T>A (p.Ile30Asn)	GJB1	Pathogenic	no assertion criteria provided
10437	NM_000166.6(GJB1):c.467T>G (p.Leu156Arg)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10438	NM_000166.6(GJB1):c.194A>G (p.Tyr65Cys)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10439	NM_000166.6(GJB1):c.37G>T (p.Val13Leu)	GJB1	Pathogenic	no assertion criteria provided
10441	NM_000166.6(GJB1):c.283G>A (p.Val95Met)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10442	NM_000166.6(GJB1):c.614A>G (p.Asn205Ser)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10444	NM_000166.6(GJB1):c.254C>G (p.Ser85Cys)	GJB1	Pathogenic	criteria provided, single submitter
10446	NM_000166.6(GJB1):c.164C>T (p.Thr55Ile)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10449	NM_001097642.3(GJB1):c.-16-511G>C	GJB1	Pathogenic	no assertion criteria provided
10451	NM_000166.6(GJB1):c.407T>C (p.Val136Ala)	GJB1	Pathogenic	no assertion criteria provided
1357566	NM_000166.6(GJB1):c.287C>G (p.Ala96Gly)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460272	NM_000166.6(GJB1):c.622del (p.Glu208fs)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155724	NM_000166.6(GJB1):c.259C>G (p.Pro87Ala)	GJB1	Pathogenic	criteria provided, single submitter
155725	NM_000166.6(GJB1):c.580A>G (p.Met194Val)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155726	NM_000166.6(GJB1):c.77C>T (p.Ser26Leu)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685848	NM_000166.6(GJB1):c.395G>A (p.Trp132Ter)	GJB1	Pathogenic	criteria provided, single submitter
1685849	NM_000166.6(GJB1):c.494T>A (p.Leu165Gln)	GJB1	Pathogenic	criteria provided, single submitter
1807289	NM_000166.6(GJB1):c.462T>A (p.Tyr154Ter)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
188174	NM_000166.6(GJB1):c.425G>A (p.Arg142Gln)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195025	NM_000166.6(GJB1):c.271G>A (p.Val91Met)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2076285	NM_000166.6(GJB1):c.52A>T (p.Thr18Ser)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21081	NM_000166.6(GJB1):c.187G>A (p.Val63Ile)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
21082	NM_000166.6(GJB1):c.223C>T (p.Arg75Trp)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 7 · 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
GJB1	Strong	X-linked	Charcot-Marie-Tooth disease X-linked dominant 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB1	Orphanet:101075	X-linked Charcot-Marie-Tooth disease type 1
GJB1	Orphanet:1175	X-linked progressive cerebellar ataxia
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
SBF1	Orphanet:363981	Charcot-Marie-Tooth disease type 4B3
DPYSL2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DNAJB2	Orphanet:314485	Young adult-onset distal hereditary motor neuropathy
DNAJB2	Orphanet:443950	DNAJB2-related Charcot-Marie-Tooth disease type 2

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB1	HGNC:4283	ENSG00000169562	P08034	Gap junction beta-1 protein	gencc,clinvar
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SBF1	HGNC:10542	ENSG00000100241	O95248	Myotubularin-related protein 5	clinvar
DPYSL2	HGNC:3014	ENSG00000092964	Q16555	Dihydropyrimidinase-related protein 2	clinvar
DRP2	HGNC:3032	ENSG00000102385	Q13474	Dystrophin-related protein 2	clinvar
DNAJB2	HGNC:5228	ENSG00000135924	P25686	DnaJ homolog subfamily B member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB1	Gap junction beta-1 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
SBF1	Myotubularin-related protein 5	Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location.
DPYSL2	Dihydropyrimidinase-related protein 2	Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration.
DRP2	Dystrophin-related protein 2	Required for normal myelination and for normal organization of the cytoplasm and the formation of Cajal bands in myelinating Schwann cells.
DNAJB2	DnaJ homolog subfamily B member 2	Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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
Phosphatase	1	14.0×	0.208
Transcription factor	1	1.4×	0.539
Other/Unknown	4	1.2×	0.539

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB1	Other/Unknown	no		Connexin, Connexin32, Connexin_N
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SBF1	Phosphatase	yes	3.1.3.16	cDENN_dom, PH_domain, GRAM
DPYSL2	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
DRP2	Transcription factor	no		Znf_ZZ, WW_dom, Spectrin_repeat
DNAJB2	Other/Unknown	no		DnaJ_domain, UIM_dom, DnaJ_domain_CS

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	2
liver	1
right lobe of liver	1
Brodmann (1909) area 23	1
frontal pole	1
middle frontal gyrus	1
left testis	1
right lobe of thyroid gland	1
right testis	1
inferior vagus X ganglion	1
substantia nigra pars compacta	1
subthalamic nucleus	1
dorsal root ganglion	1
tibial nerve	1
trigeminal ganglion	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB1	207	broad	marker	right lobe of liver, C1 segment of cervical spinal cord, liver
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SBF1	278	ubiquitous	yes	left testis, right testis, right lobe of thyroid gland
DPYSL2	301	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, substantia nigra pars compacta
DRP2	151	broad	marker	trigeminal ganglion, tibial nerve, dorsal root ganglion
DNAJB2	281	ubiquitous	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DPYSL2	2,980
DNAJB2	2,884
SBF1	1,829
GJB1	1,494
SACS	1,441
DRP2	637

Intra-cohort edges

A	B	Sources
DNAJB2	SACS	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB1	P08034	15
DPYSL2	Q16555	15
SACS	Q9NZJ4	7
DNAJB2	P25686	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SBF1	O95248	74.72
DRP2	Q13474	74.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 6 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	2	184.2×	7e-04	GJB1, DRP2
Oligomerization of connexins into connexons	1	951.7×	0.006	GJB1
Transport of connexins along the secretory pathway	1	951.7×	0.006	GJB1
Synthesis of PIPs at the ER membrane	1	571.0×	0.007	SBF1
CRMPs in Sema3A signaling	1	158.6×	0.020	DPYSL2
Rab regulation of trafficking	1	92.1×	0.024	SBF1
PI Metabolism	1	89.2×	0.024	SBF1
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.024	DRP2
Gap junction assembly	1	73.2×	0.024	GJB1
Recycling pathway of L1	1	56.0×	0.028	DPYSL2
Phospholipid metabolism	1	50.1×	0.029	SBF1
RAB GEFs exchange GTP for GDP on RABs	1	31.0×	0.042	SBF1
Membrane Trafficking	1	9.3×	0.126	SBF1
Vesicle-mediated transport	1	8.7×	0.126	SBF1
Metabolism of lipids	1	7.9×	0.129	SBF1
Metabolism	1	2.9×	0.302	SBF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of inclusion body assembly	2	561.7×	1e-04	SACS, DNAJB2
regulation of protein folding	1	2808.7×	0.006	DNAJB2
negative regulation of protein deubiquitination	1	1404.3×	0.007	DNAJB2
protein folding	2	34.5×	0.011	SACS, DNAJB2
gap junction assembly	1	351.1×	0.018	GJB1
synaptic signaling	1	255.3×	0.019	DRP2
positive regulation of ATP-dependent activity	1	234.1×	0.019	DNAJB2
regulation of protein ubiquitination	1	147.8×	0.023	DNAJB2
nervous system development	2	15.3×	0.023	GJB1, DPYSL2
negative regulation of protein binding	1	104.0×	0.027	DNAJB2
protein refolding	1	104.0×	0.027	DNAJB2
nucleobase-containing compound metabolic process	1	87.8×	0.029	DPYSL2
neuron cellular homeostasis	1	75.9×	0.031	DNAJB2
phosphatidylinositol biosynthetic process	1	61.1×	0.036	SBF1
response to unfolded protein	1	50.1×	0.041	DNAJB2
synapse organization	1	46.8×	0.041	DRP2
protein dephosphorylation	1	37.0×	0.045	SBF1
positive regulation of protein ubiquitination	1	35.5×	0.045	DNAJB2
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	35.1×	0.045	DNAJB2
regulation of protein localization	1	34.2×	0.045	DNAJB2
ERAD pathway	1	30.2×	0.048	DNAJB2
spermatid development	1	24.2×	0.055	SBF1
negative regulation of cell growth	1	24.0×	0.055	DNAJB2
cytoskeleton organization	1	22.1×	0.057	DPYSL2
central nervous system development	1	19.2×	0.063	DRP2
endocytosis	1	15.9×	0.073	DPYSL2
cell-cell signaling	1	11.6×	0.095	GJB1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	8.7×	0.121	DNAJB2
negative regulation of cell population proliferation	1	7.0×	0.144	DNAJB2
cell differentiation	1	4.8×	0.196	DPYSL2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB1	0	0
SACS	0	0
SBF1	0	0
DPYSL2	0	0
DRP2	0	0
DNAJB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DPYSL2	3	Binding:3
GJB1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SBF1	3.1.3.16	protein-serine/threonine phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	SBF1
E	Difficult family or no structure, no drug	5	GJB1, SACS, DPYSL2, DRP2, DNAJB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB1	1	—
SACS	0	—
SBF1	0	—
DPYSL2	3	—
DRP2	0	—
DNAJB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.