Charcot-Marie-Tooth disease type 1
diseaseOn this page
Also known as autosomal dominant demyelinating Charcot-Marie-Tooth diseaseCharcot-Marie-Tooth neuropathy type 1Charcot-Marie-Tooth type 1CMT1hereditary motor and sensory neuropathy type 1
Summary
Charcot-Marie-Tooth disease type 1 (MONDO:0019011) is a disease (an umbrella term covering 6 Mondo subtypes) with 24 cohort genes. The dominant Reactome pathway is EGR2 and SOX10-mediated initiation of Schwann cell myelination (4 cohort genes).
At a glance
- Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
- Umbrella term: 6 Mondo subtypes
- Cohort genes: 24
- ClinVar variants: 1,173
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Point prevalence | 1-5 / 10 000 | 17.5 | Worldwide | Validated |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Charcot-Marie-Tooth disease type 1 |
| Mondo ID | MONDO:0019011 |
| Orphanet | 65753 |
| DOID | DOID:0050538 |
| SNOMED CT | 398040009 |
| UMLS | C0751036 |
| MedGen | 155486 |
| GARD | 0012433 |
| Is cancer (heuristic) | no |
Also known as: autosomal dominant demyelinating Charcot-Marie-Tooth disease · Charcot-Marie-Tooth neuropathy type 1 · Charcot-Marie-Tooth type 1 · CMT1 · hereditary motor and sensory neuropathy type 1
Data availability: 1,173 ClinVar variants.
Disease family
An umbrella term covering 6 Mondo subtypes.
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 1
Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM
Subtypes (6): Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1E, Charcot-Marie-Tooth disease type 1C, Charcot-Marie-Tooth disease type 1D, Charcot-Marie-Tooth disease type 1F
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
600 retrieved; paginated sample, class counts are floors:
271 uncertain significance, 172 likely benign, 77 pathogenic, 32 conflicting classifications of pathogenicity, 19 pathogenic/likely pathogenic, 13 likely pathogenic, 8 benign/likely benign, 8 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1460285 | NC_000017.10:g.(?14139889)(15142928_?)del | CDRT15 | Pathogenic | criteria provided, single submitter |
| 1075624 | NM_000399.5(EGR2):c.1142G>T (p.Arg381Leu) | EGR2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16750 | NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp) | EGR2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16752 | NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp) | EGR2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 16753 | NM_000399.5(EGR2):c.1234G>A (p.Glu412Lys) | EGR2 | Pathogenic | criteria provided, single submitter |
| 219844 | NM_000399.5(EGR2):c.1226G>A (p.Arg409Gln) | EGR2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 237629 | NC_000017.11:g.(?15229777)(15260761_?)del | MIR4731 | Pathogenic | criteria provided, single submitter |
| 237630 | NM_000304.3(PMP22):c.-34-?_*1140dup1657 | MIR4731 | Pathogenic | criteria provided, single submitter |
| 1045186 | NM_000530.8(MPZ):c.437T>C (p.Val146Ala) | MPZ | 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 |
| 1070661 | NM_000530.8(MPZ):c.345del (p.His115fs) | MPZ | Pathogenic | criteria provided, single submitter |
| 1070662 | NM_000530.8(MPZ):c.171G>A (p.Trp57Ter) | MPZ | Pathogenic | criteria provided, single submitter |
| 1076512 | NM_000530.8(MPZ):c.638_639del (p.Gly213fs) | MPZ | Pathogenic | criteria provided, single submitter |
| 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 |
| 14169 | NM_000530.8(MPZ):c.188C>G (p.Ser63Cys) | 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 |
| 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 |
| 14183 | NM_000530.8(MPZ):c.103G>T (p.Asp35Tyr) | MPZ | Pathogenic/Likely 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 |
| 14188 | NM_000530.8(MPZ):c.233C>T (p.Ser78Leu) | MPZ | Pathogenic/Likely 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 |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 0 · Orphanet: 64 · 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 |
| GDAP1 | Orphanet:101097 | Autosomal recessive Charcot-Marie-Tooth disease with hoarseness |
| GDAP1 | Orphanet:101102 | Charcot-Marie-Tooth disease type 2H |
| GDAP1 | Orphanet:217055 | Autosomal recessive intermediate Charcot-Marie-Tooth disease type A |
| GDAP1 | Orphanet:99944 | Autosomal dominant Charcot-Marie-Tooth disease type 2K |
| GDAP1 | Orphanet:99948 | Charcot-Marie-Tooth disease type 4A |
| KIF1B | Orphanet:29072 | Hereditary pheochromocytoma-paraganglioma |
| KIF1B | Orphanet:99946 | Autosomal dominant Charcot-Marie-Tooth disease type 2A1 |
| LITAF | Orphanet:101083 | Charcot-Marie-Tooth disease type 1C |
| FIG4 | Orphanet:139515 | Charcot-Marie-Tooth disease type 4J |
| FIG4 | Orphanet:208441 | Bilateral parasagittal parieto-occipital polymicrogyria |
| FIG4 | Orphanet:3472 | Yunis-Varon syndrome |
| FIG4 | Orphanet:803 | Amyotrophic lateral sclerosis |
| 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 |
| TRPV4 | Orphanet:1216 | Autosomal dominant congenital benign spinal muscular atrophy |
| TRPV4 | Orphanet:263482 | Spondyloepimetaphyseal dysplasia, Maroteaux type |
| TRPV4 | Orphanet:2635 | Metatropic dysplasia |
| TRPV4 | Orphanet:431255 | Scapuloperoneal spinal muscular atrophy |
| TRPV4 | Orphanet:85169 | Familial digital arthropathy-brachydactyly |
| TRPV4 | Orphanet:86820 | Familial avascular necrosis of femoral head |
| TRPV4 | Orphanet:93304 | Autosomal dominant brachyolmia |
| TRPV4 | Orphanet:93314 | Spondylometaphyseal dysplasia, Kozlowski type |
| TRPV4 | Orphanet:99937 | Autosomal dominant Charcot-Marie-Tooth disease type 2C |
| AARS1 | Orphanet:228174 | Autosomal dominant Charcot-Marie-Tooth disease type 2N |
| AARS1 | Orphanet:33364 | Trichothiodystrophy |
| AARS1 | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| MORC2 | Orphanet:466768 | Autosomal dominant Charcot-Marie-Tooth disease type 2Z |
| LRSAM1 | Orphanet:300319 | Charcot-Marie-Tooth disease type 2P |
| SH3TC2 | Orphanet:99949 | Charcot-Marie-Tooth disease type 4C |
| 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 |
| EGR2 | Orphanet:101084 | Charcot-Marie-Tooth disease type 1D |
| EGR2 | Orphanet:64748 | Dejerine-Sottas syndrome |
| EGR2 | Orphanet:99951 | Charcot-Marie-Tooth disease type 4E |
| GARS1 | Orphanet:139536 | Distal hereditary motor neuropathy type 5 |
| GARS1 | Orphanet:99938 | Autosomal dominant Charcot-Marie-Tooth disease type 2D |
| IGHMBP2 | Orphanet:443073 | Charcot-Marie-Tooth disease type 2S |
| IGHMBP2 | Orphanet:98920 | Spinal muscular atrophy with respiratory distress type 1 |
| 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 |
Cohort genes → proteins
24 cohort genes, 22 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 24 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| PRX | HGNC:13797 | ENSG00000105227 | Q9BXM0 | Periaxin | clinvar |
| CDRT15 | HGNC:14395 | ENSG00000223510 | Q96T59 | CMT1A duplicated region transcript 15 protein | clinvar |
| GDAP1 | HGNC:15968 | ENSG00000104381 | Q8TB36 | Ganglioside-induced differentiation-associated protein 1 | clinvar |
| KIF1B | HGNC:16636 | ENSG00000054523 | O60333 | Kinesin-like protein KIF1B | clinvar |
| PRDX6 | HGNC:16753 | ENSG00000117592 | P30041 | Peroxiredoxin-6 | clinvar |
| LITAF | HGNC:16841 | ENSG00000189067 | Q99732 | Lipopolysaccharide-induced tumor necrosis factor-alpha factor | clinvar |
| FIG4 | HGNC:16873 | ENSG00000112367 | Q92562 | Polyphosphoinositide phosphatase | clinvar |
| MFN2 | HGNC:16877 | ENSG00000116688 | O95140 | Mitofusin-2 | clinvar |
| TRPV4 | HGNC:18083 | ENSG00000111199 | Q9HBA0 | Transient receptor potential cation channel subfamily V member 4 | clinvar |
| AARS1 | HGNC:20 | ENSG00000090861 | P49588 | Alanine–tRNA ligase, cytoplasmic | clinvar |
| MORC2 | HGNC:23573 | ENSG00000133422 | Q9Y6X9 | ATPase MORC2 | clinvar |
| LRSAM1 | HGNC:25135 | ENSG00000148356 | Q6UWE0 | E3 ubiquitin-protein ligase LRSAM1 | clinvar |
| SH3TC2 | HGNC:29427 | ENSG00000169247 | Q8TF17 | SH3 domain and tetratricopeptide repeat-containing protein 2 | clinvar |
| DYNC1H1 | HGNC:2961 | ENSG00000197102 | Q14204 | Cytoplasmic dynein 1 heavy chain 1 | clinvar |
| EGR2 | HGNC:3239 | ENSG00000122877 | P11161 | E3 SUMO-protein ligase EGR2 | clinvar |
| MIR4731 | HGNC:41597 | ENSG00000265110 | microRNA 4731 | clinvar | |
| GARS1 | HGNC:4162 | ENSG00000106105 | P41250 | Glycine–tRNA ligase | clinvar |
| TVP23C-CDRT4 | HGNC:42961 | ENSG00000259024 | TVP23C-CDRT4 readthrough | clinvar | |
| IGHMBP2 | HGNC:5542 | ENSG00000132740 | P38935 | DNA-binding protein SMUBP-2 | clinvar |
| MPZ | HGNC:7225 | ENSG00000158887 | P25189 | Myelin protein P0 | clinvar |
| SEPTIN9 | HGNC:7323 | ENSG00000184640 | Q9UHD8 | Septin-9 | clinvar |
| NEFL | HGNC:7739 | ENSG00000277586 | P07196 | Neurofilament light polypeptide | clinvar |
| ATF6 | HGNC:791 | ENSG00000118217 | P18850 | Cyclic AMP-dependent transcription factor ATF-6 alpha | clinvar |
| PMP22 | HGNC:9118 | ENSG00000109099 | Q01453 | Peripheral myelin protein 22 | 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. |
| GDAP1 | Ganglioside-induced differentiation-associated protein 1 | Regulates the mitochondrial network by promoting mitochondrial fission. |
| KIF1B | Kinesin-like protein KIF1B | Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules. |
| PRDX6 | Peroxiredoxin-6 | Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. |
| LITAF | Lipopolysaccharide-induced tumor necrosis factor-alpha factor | Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation. |
| FIG4 | Polyphosphoinositide phosphatase | Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). |
| MFN2 | Mitofusin-2 | Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. |
| TRPV4 | Transient receptor potential cation channel subfamily V member 4 | Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. |
| AARS1 | Alanine–tRNA ligase, cytoplasmic | Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). |
| MORC2 | ATPase MORC2 | ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex. |
| LRSAM1 | E3 ubiquitin-protein ligase LRSAM1 | E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos. |
| SH3TC2 | SH3 domain and tetratricopeptide repeat-containing protein 2 | Is involved in nerve myelination and is required for the integrity of nodes of Ranvier. |
| 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. |
| EGR2 | E3 SUMO-protein ligase EGR2 | Sequence-specific DNA-binding transcription factor. |
| 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). |
| IGHMBP2 | DNA-binding protein SMUBP-2 | 5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction. |
| MPZ | Myelin protein P0 | Is an adhesion molecule necessary for normal myelination in the peripheral nervous system. |
| SEPTIN9 | Septin-9 | Filament-forming cytoskeletal GTPase. |
| NEFL | Neurofilament light polypeptide | Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. |
| ATF6 | Cyclic AMP-dependent transcription factor ATF-6 alpha | Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 alpha), which is embedded in the endoplasmic reticulum membrane. |
| PMP22 | Peripheral myelin protein 22 | Might be involved in growth regulation, and in myelinization in the peripheral nervous system. |
Protein-family classification
Druggable: 4 · Difficult: 8 · Unknown: 12 · 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 |
|---|---|---|---|
| Ion channel | 1 | 4.7× | 0.389 |
| Scaffold/PPI | 3 | 2.2× | 0.389 |
| Transcription factor | 5 | 1.7× | 0.389 |
| Antibody/Immunoglobulin | 1 | 1.2× | 0.728 |
| Enzyme (other) | 2 | 1.0× | 0.728 |
| Other/Unknown | 12 | 0.9× | 0.783 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| PRX | Scaffold/PPI | no | PDZ, PDZ_sf, Myelin_sheath_structural | |
| CDRT15 | Other/Unknown | no | ||
| GDAP1 | Other/Unknown | no | Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1 | |
| KIF1B | Scaffold/PPI | no | FHA_dom, Kinesin_motor_dom, PH_domain | |
| PRDX6 | Enzyme (other) | yes | 1.11.1.27 | AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C |
| LITAF | Other/Unknown | no | LITAF, LITAF_fam | |
| FIG4 | Other/Unknown | no | SAC_dom, Fig4-like | |
| MFN2 | Other/Unknown | no | Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase | |
| TRPV4 | Ion channel | yes | Ankyrin_rpt, Ion_trans_dom, TrpV1-4 | |
| AARS1 | Other/Unknown | no | Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf | |
| MORC2 | Transcription factor | no | Znf_CW, HATPase_C_sf, Morc_S5 | |
| LRSAM1 | Transcription factor | no | Leu-rich_rpt, SAM, Znf_RING | |
| SH3TC2 | Scaffold/PPI | no | SH3_domain, TPR-like_helical_dom_sf, TPR_rpt | |
| DYNC1H1 | Other/Unknown | no | AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail | |
| EGR2 | Transcription factor | no | Znf_C2H2_type, EGR_N, Znf_C2H2_sf | |
| MIR4731 | Other/Unknown | no | ||
| GARS1 | Enzyme (other) | yes | 6.1.1.14 | WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly |
| TVP23C-CDRT4 | Other/Unknown | no | ||
| IGHMBP2 | Transcription factor | no | 3.6.4.12 | Znf_AN1, R3H_dom, AAA+_ATPase |
| MPZ | Antibody/Immunoglobulin | yes | Myelin_P0-rel, Ig_sub, Ig-like_dom | |
| SEPTIN9 | Other/Unknown | no | Septin, P-loop_NTPase, G_SEPTIN_dom | |
| NEFL | Other/Unknown | no | Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom | |
| ATF6 | Transcription factor | no | bZIP, bZIP_sf, ATF_bZIP_TF | |
| PMP22 | Other/Unknown | no | PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20 |
Expression context
Cohort genes with no expression data: 0.
17 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) | 24 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| sural nerve | 5 |
| olfactory bulb | 3 |
| lateral nuclear group of thalamus | 3 |
| trigeminal ganglion | 2 |
| male germ line stem cell (sensu Vertebrata) in testis | 2 |
| endothelial cell | 2 |
| secondary oocyte | 2 |
| corpus epididymis | 2 |
| mucosa of stomach | 2 |
| blood | 2 |
| apex of heart | 2 |
| cartilage tissue | 2 |
| ventricular zone | 2 |
| granulocyte | 2 |
| tibial nerve | 2 |
| dorsal root ganglion | 2 |
| left testis | 1 |
| right testis | 1 |
| oocyte | 1 |
| biceps brachii | 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 |
| CDRT15 | 127 | yes | right testis, male germ line stem cell (sensu Vertebrata) in testis, left testis | |
| GDAP1 | 244 | ubiquitous | yes | endothelial cell, secondary oocyte, oocyte |
| KIF1B | 287 | ubiquitous | marker | skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus |
| PRDX6 | 295 | ubiquitous | marker | corpus epididymis, gastrocnemius, mucosa of stomach |
| LITAF | 294 | ubiquitous | marker | blood, palpebral conjunctiva, periodontal ligament |
| FIG4 | 295 | ubiquitous | marker | middle temporal gyrus, endothelial cell, lateral nuclear group of thalamus |
| MFN2 | 297 | ubiquitous | marker | apex of heart, heart left ventricle, cardiac ventricle |
| TRPV4 | 171 | ubiquitous | marker | cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa |
| AARS1 | 301 | ubiquitous | marker | endometrium epithelium, type B pancreatic cell, frontal pole |
| MORC2 | 292 | ubiquitous | yes | cervix squamous epithelium, sperm, male germ cell |
| LRSAM1 | 192 | ubiquitous | yes | apex of heart, sural nerve, skin of leg |
| SH3TC2 | 168 | broad | marker | corpus callosum, sural nerve, C1 segment of cervical spinal cord |
| DYNC1H1 | 290 | ubiquitous | marker | cortical plate, ganglionic eminence, ventricular zone |
| EGR2 | 143 | ubiquitous | marker | gall bladder, tibial nerve, granulocyte |
| MIR4731 | 80 | yes | sural nerve, skeletal muscle tissue, blood | |
| GARS1 | 293 | ubiquitous | marker | secondary oocyte, cartilage tissue, lateral nuclear group of thalamus |
| TVP23C-CDRT4 | 133 | broad | yes | male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, islet of Langerhans |
| IGHMBP2 | 189 | ubiquitous | yes | mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer |
| MPZ | 178 | ubiquitous | marker | tibial nerve, sural nerve, olfactory bulb |
| SEPTIN9 | 293 | ubiquitous | marker | ileal mucosa, granulocyte, thymus |
| NEFL | 214 | broad | marker | dorsal root ganglion, pons, lateral nuclear group of thalamus |
| ATF6 | 283 | ubiquitous | marker | corpus epididymis, skin of hip, upper leg skin |
| PMP22 | 294 | ubiquitous | marker | olfactory bulb, trigeminal ganglion, dorsal root ganglion |
Protein interactions among cohort
Intra-cohort edges: 25.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| NEFL | 4,644 |
| DYNC1H1 | 4,215 |
| PRDX6 | 4,106 |
| MFN2 | 3,853 |
| EGR2 | 3,269 |
| AARS1 | 3,074 |
| ATF6 | 3,053 |
| GARS1 | 2,426 |
| KIF1B | 2,257 |
| SEPTIN9 | 2,119 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| AARS1 | GARS1 | string_interaction |
| DYNC1H1 | IGHMBP2 | string_interaction |
| EGR2 | PMP22 | string_interaction |
| EGR2 | PRX | string_interaction |
| FIG4 | LITAF | string_interaction |
| FIG4 | SH3TC2 | string_interaction |
| GARS1 | IGHMBP2 | string_interaction |
| GDAP1 | IGHMBP2 | string_interaction |
| GDAP1 | LITAF | string_interaction |
| GDAP1 | LRSAM1 | string_interaction |
| GDAP1 | MFN2 | string_interaction |
| GDAP1 | MORC2 | string_interaction |
| GDAP1 | SH3TC2 | string_interaction |
| IGHMBP2 | LRSAM1 | string_interaction |
| IGHMBP2 | MORC2 | string_interaction |
| IGHMBP2 | SH3TC2 | string_interaction |
| KIF1B | MFN2 | string_interaction |
| LITAF | LRSAM1 | string_interaction |
| LITAF | SH3TC2 | string_interaction |
| LRSAM1 | SH3TC2 | string_interaction |
| MORC2 | SH3TC2 | string_interaction |
| MPZ | PMP22 | biogrid_interaction |
| NEFL | PMP22 | string_interaction |
| PMP22 | PRX | string_interaction |
| PMP22 | SH3TC2 | string_interaction |
Structural data
PDB: 14 · AlphaFold-only: 8 · No structure: 2
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| DYNC1H1 | Q14204 | 97 |
| TRPV4 | Q9HBA0 | 19 |
| GARS1 | P41250 | 14 |
| MORC2 | Q9Y6X9 | 9 |
| GDAP1 | Q8TB36 | 8 |
| AARS1 | P49588 | 6 |
| IGHMBP2 | P38935 | 4 |
| PRDX6 | P30041 | 3 |
| MFN2 | O95140 | 3 |
| SEPTIN9 | Q9UHD8 | 3 |
| MPZ | P25189 | 2 |
| PRX | Q9BXM0 | 1 |
| KIF1B | O60333 | 1 |
| FIG4 | Q92562 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| PMP22 | Q01453 | 89.87 |
| SH3TC2 | Q8TF17 | 78.63 |
| LRSAM1 | Q6UWE0 | 78.47 |
| NEFL | P07196 | 73.66 |
| LITAF | Q99732 | 70.60 |
| ATF6 | P18850 | 56.09 |
| CDRT15 | Q96T59 | 52.21 |
| EGR2 | P11161 | 49.02 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 83. Enrichment computed across 24 evidence-associated genes (17 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 17 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 | 4 | 86.7× | 9e-06 | PRX, EGR2, MPZ, PMP22 |
| Cytosolic tRNA aminoacylation | 2 | 51.7× | 0.028 | AARS1, GARS1 |
| Miro GTPase Cycle | 1 | 134.3× | 0.149 | MFN2 |
| ATF6 (ATF6-alpha) activates chaperones | 1 | 112.0× | 0.149 | ATF6 |
| RHOT2 GTPase cycle | 1 | 96.0× | 0.149 | MFN2 |
| ATF6 (ATF6-alpha) activates chaperone genes | 1 | 67.2× | 0.149 | ATF6 |
| Mitophagy | 1 | 61.1× | 0.149 | MFN2 |
| Synthesis of PIPs at the late endosome membrane | 1 | 56.0× | 0.149 | FIG4 |
| PERK regulates gene expression | 1 | 48.0× | 0.149 | ATF6 |
| Synthesis of PIPs at the early endosome membrane | 1 | 42.0× | 0.149 | FIG4 |
| Synthesis of PIPs at the Golgi membrane | 1 | 37.3× | 0.149 | FIG4 |
| Modulation of host responses by IFN-stimulated genes | 1 | 35.4× | 0.149 | ATF6 |
| Ras activation upon Ca2+ influx through NMDA receptor | 1 | 33.6× | 0.149 | NEFL |
| Unblocking of NMDA receptors, glutamate binding and activation | 1 | 32.0× | 0.149 | NEFL |
| Negative regulation of NMDA receptor-mediated neuronal transmission | 1 | 32.0× | 0.149 | NEFL |
| Mitochondrial tRNA aminoacylation | 1 | 30.5× | 0.149 | GARS1 |
| Class I peroxisomal membrane protein import | 1 | 30.5× | 0.149 | GDAP1 |
| Factors involved in megakaryocyte development and platelet production | 2 | 7.8× | 0.149 | KIF1B, MFN2 |
| Long-term potentiation | 1 | 28.0× | 0.154 | NEFL |
| Fatty acyl-CoA biosynthesis | 1 | 25.8× | 0.154 | MORC2 |
| TRP channels | 1 | 24.0× | 0.154 | TRPV4 |
| ATF4 activates genes in response to endoplasmic reticulum stress | 1 | 24.0× | 0.154 | ATF6 |
| Regulation of endogenous retroelements | 1 | 21.7× | 0.155 | MORC2 |
| Unfolded Protein Response (UPR) | 1 | 21.0× | 0.155 | ATF6 |
| PINK1-PRKN Mediated Mitophagy | 1 | 21.0× | 0.155 | MFN2 |
| Detoxification of Reactive Oxygen Species | 1 | 17.7× | 0.170 | PRDX6 |
| tRNA Aminoacylation | 1 | 16.8× | 0.170 | AARS1 |
| NGF-stimulated transcription | 1 | 16.8× | 0.170 | EGR2 |
| Selective autophagy | 1 | 16.4× | 0.170 | MFN2 |
| Assembly and cell surface presentation of NMDA receptors | 1 | 14.9× | 0.178 | NEFL |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| myelin assembly | 2 | 187.2× | 0.005 | FIG4, PMP22 |
| retrograde axonal transport | 2 | 153.2× | 0.005 | DYNC1H1, NEFL |
| peripheral nervous system myelin maintenance | 2 | 153.2× | 0.005 | PRX, SH3TC2 |
| tRNA aminoacylation for protein translation | 2 | 84.3× | 0.010 | AARS1, GARS1 |
| mitochondrial fusion | 2 | 84.3× | 0.010 | GDAP1, MFN2 |
| rhombomere 3 structural organization | 1 | 842.6× | 0.014 | EGR2 |
| rhombomere 3 formation | 1 | 842.6× | 0.014 | EGR2 |
| rhombomere 5 structural organization | 1 | 842.6× | 0.014 | EGR2 |
| rhombomere 5 formation | 1 | 842.6× | 0.014 | EGR2 |
| hyperosmotic salinity response | 1 | 842.6× | 0.014 | TRPV4 |
| intermediate filament polymerization or depolymerization | 1 | 842.6× | 0.014 | NEFL |
| blood vessel endothelial cell delamination | 1 | 842.6× | 0.014 | TRPV4 |
| regulation of cytoplasmic translational fidelity | 1 | 842.6× | 0.014 | AARS1 |
| regulation of ERBB signaling pathway | 1 | 842.6× | 0.014 | SH3TC2 |
| positive regulation of ATF6-mediated unfolded protein response | 1 | 842.6× | 0.014 | ATF6 |
| obsolete protein targeting to mitochondrion | 2 | 58.1× | 0.014 | GDAP1, MFN2 |
| peripheral nervous system development | 2 | 58.1× | 0.014 | EGR2, PMP22 |
| alanyl-tRNA aminoacylation | 1 | 421.3× | 0.016 | AARS1 |
| rhythmic behavior | 1 | 421.3× | 0.016 | EGR2 |
| regulation of macrophage cytokine production | 1 | 421.3× | 0.016 | LITAF |
| positive regulation of Schwann cell differentiation | 1 | 421.3× | 0.016 | EGR2 |
| vasopressin secretion | 1 | 421.3× | 0.016 | TRPV4 |
| positive regulation of striated muscle contraction | 1 | 421.3× | 0.016 | TRPV4 |
| regulation of response to osmotic stress | 1 | 421.3× | 0.016 | TRPV4 |
| mitochondrial glycyl-tRNA aminoacylation | 1 | 421.3× | 0.016 | GARS1 |
| cell aggregation | 1 | 421.3× | 0.016 | MPZ |
| calcium ion import into cytosol | 1 | 421.3× | 0.016 | TRPV4 |
| response to sodium arsenite | 1 | 421.3× | 0.016 | NEFL |
| response to acrylamide | 1 | 421.3× | 0.016 | NEFL |
| neuromuscular process controlling balance | 2 | 33.0× | 0.016 | AARS1, NEFL |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 19
Druggability breadth: 10 of 24 evidence-associated genes (42%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| SEPTIN9 | BARICITINIB |
| PMP22 | PROGESTERONE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| PMP22 | 213 | 4 |
| TRPV4 | 6 | 3 |
| SEPTIN9 | 3 | 4 |
| DYNC1H1 | 1 | 2 |
| GARS1 | 1 | 3 |
| PRX | 0 | 0 |
| CDRT15 | 0 | 0 |
| GDAP1 | 0 | 0 |
| KIF1B | 0 | 0 |
| PRDX6 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| BARICITINIB | 4 | SEPTIN9 |
| PROGESTERONE | 4 | PMP22 |
| CLOTRIMAZOLE | 4 | PMP22 |
| OXAPROZIN | 4 | PMP22 |
| SALMETEROL XINAFOATE | 4 | PMP22 |
| AMIODARONE HYDROCHLORIDE | 4 | PMP22 |
| TRIHEXYPHENIDYL HYDROCHLORIDE | 4 | PMP22 |
| AMOXAPINE | 4 | PMP22 |
| RALOXIFENE HYDROCHLORIDE | 4 | PMP22 |
| IDARUBICIN | 4 | PMP22 |
| OXYBUTYNIN CHLORIDE | 4 | PMP22 |
| PINACIDIL ANHYDROUS | 4 | PMP22 |
| NICARDIPINE HYDROCHLORIDE | 4 | PMP22 |
| PILOCARPINE HYDROCHLORIDE | 4 | PMP22 |
| PROTRIPTYLINE HYDROCHLORIDE | 4 | PMP22 |
| BENZTROPINE MESYLATE | 4 | PMP22 |
| BUSPIRONE HYDROCHLORIDE | 4 | PMP22 |
| DOBUTAMINE HYDROCHLORIDE | 4 | PMP22 |
| PROMAZINE HYDROCHLORIDE | 4 | PMP22 |
| DICYCLOMINE HYDROCHLORIDE | 4 | PMP22 |
| GUANFACINE HYDROCHLORIDE | 4 | PMP22 |
| HYDROCORTISONE SODIUM SUCCINATE | 4 | PMP22 |
| BROMOCRIPTINE MESYLATE | 4 | PMP22 |
| DIHYDROERGOTAMINE MESYLATE | 4 | PMP22 |
| DOXAZOSIN MESYLATE | 4 | PMP22 |
| CYCLOBENZAPRINE HYDROCHLORIDE | 4 | PMP22 |
| DEXBROMPHENIRAMINE MALEATE | 4 | PMP22 |
| CLOMIPRAMINE HYDROCHLORIDE | 4 | PMP22 |
| CHLORMEZANONE | 4 | PMP22 |
| PROMETHAZINE HYDROCHLORIDE | 4 | PMP22 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 3.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| TRPV4 | 99 | Binding:94, Functional:5 |
| PRDX6 | 15 | Binding:15 |
| GARS1 | 8 | Binding:8 |
| DYNC1H1 | 7 | Binding:7 |
| MFN2 | 3 | Binding:3 |
| AARS1 | 2 | Binding:2 |
| SEPTIN9 | 2 | Binding:2 |
| KIF1B | 1 | Binding:1 |
| LITAF | 1 | Binding:1 |
| PMP22 | 1 | Functional:1 |
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 |
| IGHMBP2 | 3.6.4.12 | DNA helicase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 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) |
|---|---|---|
| BARICITINIB | 4 | SEPTIN9 |
| PROGESTERONE | 4 | PMP22 |
| CLOTRIMAZOLE | 4 | PMP22 |
| OXAPROZIN | 4 | PMP22 |
| SALMETEROL XINAFOATE | 4 | PMP22 |
| AMIODARONE HYDROCHLORIDE | 4 | PMP22 |
| TRIHEXYPHENIDYL HYDROCHLORIDE | 4 | PMP22 |
| AMOXAPINE | 4 | PMP22 |
| RALOXIFENE HYDROCHLORIDE | 4 | PMP22 |
| IDARUBICIN | 4 | PMP22 |
| OXYBUTYNIN CHLORIDE | 4 | PMP22 |
| PINACIDIL ANHYDROUS | 4 | PMP22 |
| NICARDIPINE HYDROCHLORIDE | 4 | PMP22 |
| PILOCARPINE HYDROCHLORIDE | 4 | PMP22 |
| PROTRIPTYLINE HYDROCHLORIDE | 4 | PMP22 |
| BENZTROPINE MESYLATE | 4 | PMP22 |
| BUSPIRONE HYDROCHLORIDE | 4 | PMP22 |
| DOBUTAMINE HYDROCHLORIDE | 4 | PMP22 |
| PROMAZINE HYDROCHLORIDE | 4 | PMP22 |
| DICYCLOMINE HYDROCHLORIDE | 4 | PMP22 |
| GUANFACINE HYDROCHLORIDE | 4 | PMP22 |
| HYDROCORTISONE SODIUM SUCCINATE | 4 | PMP22 |
| BROMOCRIPTINE MESYLATE | 4 | PMP22 |
| DIHYDROERGOTAMINE MESYLATE | 4 | PMP22 |
| DOXAZOSIN MESYLATE | 4 | PMP22 |
| CYCLOBENZAPRINE HYDROCHLORIDE | 4 | PMP22 |
| DEXBROMPHENIRAMINE MALEATE | 4 | PMP22 |
| CLOMIPRAMINE HYDROCHLORIDE | 4 | PMP22 |
| CHLORMEZANONE | 4 | PMP22 |
| PROMETHAZINE HYDROCHLORIDE | 4 | PMP22 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | SEPTIN9, PMP22 |
| B | Phased (≥1) drug, not yet approved | 3 | TRPV4, DYNC1H1, GARS1 |
| C | Druggable family + PDB, no drug | 2 | PRDX6, MPZ |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 17 | PRX, CDRT15, GDAP1, KIF1B, LITAF, FIG4, MFN2, AARS1, MORC2, LRSAM1 (+7 more) |
Undrugged target profiles
19 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| PRX | 0 | — |
| CDRT15 | 0 | — |
| GDAP1 | 0 | — |
| KIF1B | 1 | — |
| PRDX6 | 15 | — |
| LITAF | 1 | — |
| FIG4 | 0 | — |
| MFN2 | 3 | — |
| AARS1 | 2 | — |
| MORC2 | 0 | — |
| LRSAM1 | 0 | — |
| SH3TC2 | 0 | — |
| EGR2 | 0 | — |
| MIR4731 | 0 | — |
| TVP23C-CDRT4 | 0 | — |
| IGHMBP2 | 0 | — |
| MPZ | 0 | — |
| NEFL | 0 | — |
| ATF6 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.