Charcot-Marie-Tooth disease type 2B2

Summary

Charcot-Marie-Tooth disease type 2B2 (MONDO:0011570) is a disease caused by PNKP (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNKP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 35
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2B2
Mondo ID	MONDO:0011570
MeSH	C537991
OMIM	605589
Orphanet	101101
DOID	DOID:0110179
ICD-11	2009111705
SNOMED CT	719981005
UMLS	C1854150
MedGen	381352
GARD	0001249
Is cancer (heuristic)	no

Also known as: AR-CMT2B2 · ARCMT2B · autosomal recessive axonal Charcot-Marie-Tooth disease type 2B2 · autosomal recessive axonal CMT4C3 · Charcot Marie Tooth disease type 2B2 · Charcot-Marie-Tooth disease type 2B2 · Charcot-Marie-Tooth disease, axonal, autosomal recessive, B2 · Charcot-Marie-Tooth disease, axonal, type 2B2 · Charcot-Marie-Tooth disease, type 2B2 · CMT 2B2 · CMT2B2

Data availability: 35 ClinVar variants · 4 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 type 2B2

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

35 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 8 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign, 2 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453676	NM_007254.4(PNKP):c.721G>T (p.Glu241Ter)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190219	NM_007254.4(PNKP):c.1221_1223del (p.Thr408del)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206429	NM_007254.4(PNKP):c.1317_1321dup (p.Ala441fs)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293589	NM_007254.4(PNKP):c.199-10_203delinsTCTGAGGGGT	PNKP	Pathogenic	criteria provided, single submitter
436354	NM_007254.4(PNKP):c.636+1G>T	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065388	NM_007254.4(PNKP):c.637-1G>C	PNKP	Likely pathogenic	criteria provided, single submitter
4277707	NM_007254.4(PNKP):c.1317_1323del (p.Ala441fs)	PNKP	Likely pathogenic	criteria provided, single submitter
4845667	NM_007254.4(PNKP):c.1485dup (p.Ser496fs)	PNKP	Likely pathogenic	criteria provided, single submitter
1324	NM_030973.4(MED25):c.1004C>T (p.Ala335Val)	MED25	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1348787	NM_030973.4(MED25):c.602dup (p.Ala202fs)	MED25	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421749	NM_030973.4(MED25):c.316G>A (p.Gly106Arg)	MED25	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
973234	NM_030973.4(MED25):c.1628_1637del (p.Asn543fs)	MED25	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159794	NM_007254.4(PNKP):c.416G>A (p.Arg139His)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
206401	NM_007254.4(PNKP):c.1029+2T>C	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391407	NM_007254.4(PNKP):c.1009G>C (p.Glu337Gln)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
854429	NM_007254.4(PNKP):c.1549C>T (p.Gln517Ter)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216779	NM_030973.4(MED25):c.1438C>G (p.Leu480Val)	MED25	Uncertain significance	criteria provided, multiple submitters, no conflicts
329881	NM_030973.4(MED25):c.1101+4G>A	MED25	Uncertain significance	criteria provided, multiple submitters, no conflicts
655582	NM_030973.4(MED25):c.751G>A (p.Ala251Thr)	MED25	Uncertain significance	criteria provided, multiple submitters, no conflicts
974688	NM_030973.4(MED25):c.949G>T (p.Gly317Cys)	MED25	Uncertain significance	criteria provided, multiple submitters, no conflicts
194242	NM_007254.4(PNKP):c.1177C>T (p.His393Tyr)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
197287	NM_007254.4(PNKP):c.290A>G (p.Asn97Ser)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
198198	NM_007254.4(PNKP):c.625G>A (p.Glu209Lys)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
206415	NM_007254.4(PNKP):c.1391G>C (p.Arg464Pro)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
3584058	NM_007254.4(PNKP):c.1316G>A (p.Arg439Gln)	PNKP	Uncertain significance	criteria provided, single submitter
4292301	NM_007254.4(PNKP):c.1189G>A (p.Asp397Asn)	PNKP	Uncertain significance	criteria provided, single submitter
471506	NM_007254.4(PNKP):c.58C>A (p.Pro20Thr)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
221177	NM_030973.4(MED25):c.1483-7C>T	MED25	Benign	criteria provided, multiple submitters, no conflicts
329886	NM_030973.4(MED25):c.1675-7C>T	MED25	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
698358	NM_030973.4(MED25):c.633A>T (p.Thr211=)	MED25	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · 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
PNKP	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 2B2	11
MED25	Supportive	Autosomal recessive	Charcot-Marie-Tooth disease type 2B2	7
MED9	Supportive	Autosomal recessive	Charcot-Marie-Tooth disease type 2B2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED25	Orphanet:464738	Basel-Vanagaite-Smirin-Yosef syndrome
MED25	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
PNKP	Orphanet:101101	Charcot-Marie-Tooth disease type 2B2
PNKP	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PNKP	Orphanet:459033	Ataxia-oculomotor apraxia type 4

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED9	HGNC:25487	ENSG00000141026	Q9NWA0	Mediator of RNA polymerase II transcription subunit 9	gencc,clinvar
MED25	HGNC:28845	ENSG00000104973	Q71SY5	Mediator of RNA polymerase II transcription subunit 25	gencc,clinvar
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED9	Mediator of RNA polymerase II transcription subunit 9	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
MED25	Mediator of RNA polymerase II transcription subunit 25	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	28.0×	0.071
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED9	Other/Unknown	no		Med9, Med7/Med21-like, MED9_metazoa
MED25	Other/Unknown	no		Med25_PTOV, Mediator_Med25_SD1, Mediator_Med25_VWA
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
oocyte	1
right testis	1
secondary oocyte	1
granulocyte	1
right adrenal gland cortex	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED9	195	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
MED25	269	ubiquitous	marker	oocyte, secondary oocyte, right testis
PNKP	259	ubiquitous	marker	right uterine tube, granulocyte, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNKP	2,445
MED25	1,883
MED9	1,069

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MED9	Q9NWA0	11
MED25	Q71SY5	10
PNKP	Q96T60	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Respiratory Syncytial Virus Infection Pathway	2	131.3×	6e-04	MED9, MED25
RSV-host interactions	2	104.3×	6e-04	MED9, MED25
Adipogenesis	2	104.3×	6e-04	MED9, MED25
Regulation of lipid metabolism by PPARalpha	2	94.0×	6e-04	MED9, MED25
Transcriptional regulation of white adipocyte differentiation	2	86.5×	6e-04	MED9, MED25
PPARA activates gene expression	2	62.9×	9e-04	MED9, MED25
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	543.8×	0.004	PNKP
Metabolism of lipids	2	21.0×	0.005	MED9, MED25
Viral Infection Pathways	2	20.5×	0.005	MED9, MED25
Infectious disease	2	16.6×	0.008	MED9, MED25
Developmental Biology	2	9.6×	0.020	MED9, MED25
Disease	2	8.7×	0.022	MED9, MED25
Metabolism	2	7.7×	0.026	MED9, MED25
RNA Polymerase II Transcription	1	7.5×	0.146	MED25
Gene expression (Transcription)	1	6.0×	0.169	MED25
Generic Transcription Pathway	1	5.0×	0.186	MED25

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of transcription elongation by RNA polymerase II	2	200.6×	2e-04	MED9, MED25
RNA polymerase II preinitiation complex assembly	2	181.2×	2e-04	MED9, MED25
positive regulation of transcription initiation by RNA polymerase II	2	181.2×	2e-04	MED9, MED25
positive regulation of mediator complex assembly	1	5617.3×	8e-04	MED25
positive regulation of chromatin binding	1	936.2×	0.004	MED25
response to radiation	1	401.2×	0.006	PNKP
base-excision repair, gap-filling	1	374.5×	0.006	PNKP
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.006	PNKP
DNA-templated DNA replication	1	187.2×	0.009	PNKP
positive regulation of telomere maintenance	1	170.2×	0.009	PNKP
negative regulation of fibroblast proliferation	1	165.2×	0.009	MED25
double-strand break repair via nonhomologous end joining	1	140.4×	0.010	PNKP
nucleotide-excision repair	1	127.7×	0.010	PNKP
response to oxidative stress	1	43.5×	0.028	PNKP
DNA repair	1	21.3×	0.052	PNKP
negative regulation of transcription by RNA polymerase II	1	5.9×	0.170	MED25
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	MED25

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MED9	0	0
MED25	0	0
PNKP	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
PNKP	8	Binding:8
MED25	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	PNKP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MED9, MED25

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MED9	0	—
MED25	3	—
PNKP	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease