GeneBe

PMP22

protein-coding

peripheral myelin protein 22, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Previous symbols:
  • CMT1A

MANE transcript

NM_000304.4

Inheritance

AD, AR

ClinVar variants

P:104U:146B:60

Top phenotype

Roussy-Levy syndrome; Charcot-Marie-Tooth syndrome, type 1A; Charcot-Marie-Tooth syndrome with deafness (type 1E); Neuropathy, hereditary, with liability to pressurve palsies; Dejerine-Sottas disease; Neuropathy, inflammatory demyelinating

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:15,229,773-15,272,292

External References & Databases

Ensembl (ENSG00000109099)NCBI Gene (5376)OMIM (601097)HGNC:9118GenCCUniProt (Q01453)AlphaFoldClinVar (PMP22)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~42.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 1ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: Ambry Genetics

hereditary neuropathy with liability to pressure palsiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008087

Submitter: Ambry Genetics

hereditary neuropathy with liability to pressure palsiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008087

Submitter: Labcorp Genetics (formerly Invitae)

hereditary neuropathy with liability to pressure palsiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008087

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 1ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: Orphanet

Charcot-Marie-Tooth disease type 1ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: ClinGen

The PMP22 duplication was first reported in relation to autosomal dominant Charcot-Marie-Tooth disease type 1A in 1992 (Patel et al., PMID: 1303228). Before the introduction of increased dosage effect of PMP22 gene and its duplication causal to CMT1A, there were reports of families with autosomal dominant pattern of inheritance among affected individuals with slowed conduction velocities unlinked to the "Duffy Locus" on chromosome 1 (PMIDs: 6651251, 6865476). Later on, several studies found positive linkage to markers on chromosome 17 in patients with CMT1A clinical and electrophysiological features (though highly variable in severity, age of onset and progression) and DNA duplication at 17pl 1.2-pl2 region (PMIDs: 1822787, 2707366, 2589322, 2239969, etc). Several independent studies demonstrated the localization of the PMP22 gene in this region and introduced it as a candidate gene responsible for demyelinating CMT1A (PMIDs: 1297450, 1303229). There have been numerous publications describing hundreds of patients with CMT1A and the duplication of PMP22 gene or the chromosomal region containing this gene - we detail 10 probands with over 40 family members (PMIDs: 1453432, 8644705). The mechanism of demyelination in CMT1A is gene-dosage effect with toxic gain of function caused by PMP22 overexpression, mainly because the components of myelin are stoichiometrically balanced and can be disturbed due to any faulty expression of myelin sheath components. The pathomechanism of PMP22 overexpression and its gene-disease association has been demonstrated through various in vitro assays as well as animal models (PMIDs: 9467003, 8630243). Much more evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, PMP22 duplication is DEFINITIVELY associated with autosomal dominant Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease type 1ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

hereditary neuropathy with liability to pressure palsiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008087

Submitter: ClinGen

PMP22 was first reported in relation to autosomal dominant Hereditary Neuropathy with liability to Pressure Palsies (HNPP) in 1993 (Chance et al., PMID: 8422677). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we decided to split this disease with the PMP22 duplication causing Charcot Marie Tooth Type 1A and point mutations causing CMT1E. The split curation for CMT1A and CMT1E has been curated separately. The most common genetic variant associated with HNPP is a 1.5MB deletion affecting PMP22 and has been seen in many patients over time. This decreases PMP22 protein levels and affects patients through a dosage sensitive mechanism. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models involving mice. In mice models with PMP22 deletion, nerves recapitulate tomacula swellings seen in HNPP patients, and decreased nerve conduction velocities. In summary, there is definitive and longstanding evidence supporting the relationship between PMP22 deletion and HNPP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease type 1ESUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007311

Submitter: Orphanet

hereditary neuropathy with liability to pressure palsiesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008087

Submitter: Orphanet

Charcot-Marie-Tooth disease type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007790

Submitter: Orphanet

Charcot-Marie-Tooth disease type 1EMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007311

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 1ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007311

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 1ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007311

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007790

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 1ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 1ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007309

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Roussy-Levy syndrome; Charcot-Marie-Tooth syndrome, type 1A; Charcot-Marie-Tooth syndrome with deafness (type 1E); Neuropathy, hereditary, with liability to pressurve palsies; Dejerine-Sottas disease; Neuropathy, inflammatory demyelinatingAD/AR

Manifestation: Audiologic/Otolaryngologic; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: CMT, 1A can be due to a common 17p11.2 duplication; The variant type (eg, deletions vs. duplications) influences the phenotype; Compound heterozygous variants have been described

Refs: 13184660; 7139106; 2290479; 1349106; 1303281; 8422677; 7834893; 7903071; 8012388; 8210227; 7501152; 7666403; 8644705; 8981968; 9208274; 9179161; 9391880; 9543325; 9703447; 10489052; 10330345; 10211478; 11376203; 11835375; 12439896; 12499508; 12427913; 12084875; 12578939; 15205993; 17620487; 18698610; 19705173; 19888301; 20301566; 20301384; 22006697; 22190321; 22382358Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PMP22 variants in ClinVar

23 Conditions Cataloged
Charcot-Marie-Tooth disease, type ITotal: 246
not providedTotal: 119
Charcot-Marie-Tooth diseaseTotal: 82
Inborn genetic diseasesTotal: 40
Charcot-Marie-Tooth disease, type IATotal: 35
Dejerine-Sottas diseaseTotal: 31
Hereditary liability to pressure palsiesTotal: 31
Charcot-Marie-Tooth disease type 1ETotal: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000304.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
53
clinvar
 56
missense
18
clinvar
28
clinvar
115
clinvar
7
clinvar
 168
nonsense
10
clinvar
5
clinvar
3
clinvar
 18
start loss
2
clinvar
 2
frameshift
20
clinvar
9
clinvar
14
clinvar
 43
splice donor/acceptor (+/-2bp)
9
clinvar
4
clinvar
10
clinvar
 23
Total5846146600310

Highest pathogenic variant AF is 0.0000065717704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000304.4RefSeqNP_000295.14MANE Select
ENST00000312280.9EnsemblENSP00000308937.34MANE Select
NM_001281455.2RefSeqNP_001268384.14Standard
NM_001281456.2RefSeqNP_001268385.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neural Crest Differentiation
  • a6b1 and a6b4 Integrin signaling

Biological Process

  • chemical synaptic transmission
  • peripheral nervous system development
  • cell death
  • negative regulation of cell population proliferation
  • negative regulation of neuron projection development

Molecular Function

  • protein binding

Cellular Component

  • plasma membrane
  • bicellular tight junction
  • integral component of membrane
  • compact myelin

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000395938
Coding exons
4
Length
35549
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.4177990.10.8760.000005381023
Missense (PolyPhen)3040.1010.74811455
Synonymous-0.2824441.71.060.00000286335
Loss of Function2.5807.740.003.46e-780

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Might be involved in growth regulation, and in myelinization in the peripheral nervous system.;
Disease
DISEASE: Charcot-Marie-Tooth disease 1A (CMT1A) [MIM:118220]: A dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. {ECO:0000269|PubMed:10489052, ECO:0000269|PubMed:10737979, ECO:0000269|PubMed:11140841, ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:12402337, ECO:0000269|PubMed:12497641, ECO:0000269|PubMed:1303281, ECO:0000269|PubMed:15205993, ECO:0000269|PubMed:8252046, ECO:0000269|PubMed:8510709, ECO:0000269|PubMed:8615087, ECO:0000269|PubMed:8655153, ECO:0000269|PubMed:8777804, ECO:0000269|PubMed:9040744}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dejerine-Sottas syndrome (DSS) [MIM:145900]: A severe degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. Characterized by motor and sensory neuropathy with very slow nerve conduction velocities, increased cerebrospinal fluid protein concentrations, hypertrophic nerve changes, delayed age of walking as well as areflexia. There are both autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome. {ECO:0000269|PubMed:10211478, ECO:0000269|PubMed:10663978, ECO:0000269|PubMed:11438991, ECO:0000269|PubMed:12090401, ECO:0000269|PubMed:7675244, ECO:0000269|PubMed:7728152, ECO:0000269|PubMed:8252046, ECO:0000269|PubMed:8275092, ECO:0000269|PubMed:8995589, ECO:0000269|PubMed:9004143, ECO:0000269|PubMed:9055797, ECO:0000269|PubMed:9187667, ECO:0000269|PubMed:9452053, ECO:0000269|PubMed:9544841, ECO:0000269|PubMed:9585367, ECO:0000269|PubMed:9633821}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary neuropathy with liability to pressure palsies (HNPP) [MIM:162500]: A neurologic disorder characterized by transient episodes of decreased perception or peripheral nerve palsies after slight traction, compression or minor traumas. {ECO:0000269|PubMed:12796555, ECO:0000269|PubMed:15205993, ECO:0000269|PubMed:9748013}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 1E (CMT1E) [MIM:118300]: An autosomal dominant form of Charcot-Marie-Tooth disease characterized by the association of sensorineural hearing loss with peripheral demyelinating neuropathy. {ECO:0000269|PubMed:10330345, ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:12578939, ECO:0000269|PubMed:15099592}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Inflammatory demyelinating polyneuropathy (IDP) [MIM:139393]: Putative autoimmune disorder presenting in an acute (AIDP) or chronic form (CIDP). The acute form is also known as Guillain-Barre syndrome. {ECO:0000269|PubMed:12439896}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.417

Intolerance Scores

LoFtool
0.0761
RVIS EVS
0.28
RVIS percentile EVS
71.08

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.741

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.