GeneBe

MPZ

protein-coding

myelin protein zero, the group of V-set domain containing|Ig-like cell adhesion molecule family

Gene summary

This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major structural protein of the peripheral myelin sheath. The encoded protein contains a large hydrophobic extracellular domain and a smaller basic intracellular domain, which are essential for the formation and stabilization of the multilamellar structure of the compact myelin. Mutations in this gene are associated with autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B) and other polyneuropathies, such as Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN). A recent study showed that two isoforms are produced from the same mRNA by use of alternative in-frame translation termination codons via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2015]

Previous symbols:
  • CMT1
  • CMT1B

MANE transcript

NM_000530.8

Inheritance

AD, SD

ClinVar variants

P:233U:292B:74

Top phenotype

Charcot-Marie-Tooth disease, dominant intermediate 3; Charcot-Marie-Tooth disease, axonal, type 2J; Charcot-Marie-Tooth disease, axonal, type 2I; Neuropathy, congenital hypomyelinating 1; Roussy-Levy syndrome; Dejerine-Sottas disease; Charcot-Marie-Tooth disease, demyelinating, type 1B; Hypomyelinating neuropathy, congenital, 2

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr1:161,304,735-161,309,968

External References & Databases

Ensembl (ENSG00000158887)NCBI Gene (4359)OMIM (159440)HGNC:7225GenCCUniProt (P25189)AlphaFoldClinVar (MPZ)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 1BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007307

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007790

Submitter: Orphanet

Charcot-Marie-Tooth disease type 2ISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011889

Submitter: Orphanet

Charcot-Marie-Tooth disease type 2JSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011903

Submitter: Orphanet

Charcot-Marie-Tooth diseaseSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0015626

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 1BSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007307

Submitter: Orphanet

neuropathy, congenital hypomyelinating, 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020765

Submitter: G2P

autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic painSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017937

Submitter: Orphanet

Charcot-Marie-Tooth disease dominant intermediate DSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011909

Submitter: Orphanet

Charcot-Marie-Tooth disease type 1BDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007307

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.

Charcot-Marie-Tooth diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015626

Submitter: ClinGen

MPZ was first reported in relation to Autosomal Dominant Charcot-Marie-Tooth Disease in 1993 (Hayaska et al., PMID: 7693129). Before the causal gene itself was characterized, examples of demyelinating neuropathies of variable severity with linkage to the "Duffy Locus" on chromosome 1 were relatively well-characterized (PMIDs: 6952764, 7130990, 4020397, etc.). Two independent groups examining the region mapped the human gene encoding a primary structural component protein in compact myelin, Myelin Protein Zero, to that region of the genome and verified that the causal variants in many neuropathy cases were in this MPZ gene (PMIDs: 7693129, 7504284). Over 200 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes a more than sufficient amount of case-level data, segregation data, and experimental data. There have been numerous publications describing MPZ patients and the variants they harbor - we detail 11 probands with over 50 family members. Much more evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. The mechanism for disease is heterozygous gain of function, with pathogenic mutations having one of several potential effects on the overall system. Many variants affect specifically myelin compaction, disrupting the myelination process via localization other than the plasma membrane or by dominant-negative alteration of the overall myelin sheath. Notably, MPZ variants can also cause a phenotypically axonal neuropathy, potentially via disruption of Schwann cell - neuron interaction, however the pathomechanism is not fully understood (PMID: 16775378). This gene-disease association is additionally supported by multiple mouse models, expression studies, in vitro functional assays, and MPZ interactions with PMP22, another important structural protein. Multiple mouse models with known pathogenic MPZ mutations have been developed and well-characterized over the years. Functional assays have demonstrated that disruption of MPZ expression via antisense MPZ mRNA causes significantly disrupted myelination. In summary, MPZ 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.

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, dominant intermediate 3; Charcot-Marie-Tooth disease, axonal, type 2J; Charcot-Marie-Tooth disease, axonal, type 2I; Neuropathy, congenital hypomyelinating 1; Roussy-Levy syndrome; Dejerine-Sottas disease; Charcot-Marie-Tooth disease, demyelinating, type 1B; Hypomyelinating neuropathy, congenital, 2AD

Manifestation: 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: Individuals with biallelic variants have also been described

Refs: 7693129; 8310815; 8664899; 8816708; 9595994; 9537424; 10319895; 10329755; 10071056; 10406984; 10214757; 10553995; 10965800; 11080237; 10764043; 11835375; 14638973; 15159512; 15184631; 15326256; 15642860; 16488608; 16775239; 17663472; 17825553; 21326314; 21280073; 22222859; 22622165; 22633464; 22691094; 22734905Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MPZ variants in ClinVar

39 Conditions Cataloged
Charcot-Marie-Tooth disease, type ITotal: 470
Charcot-Marie-Tooth diseaseTotal: 192
not providedTotal: 184
Charcot-Marie-Tooth disease type 1BTotal: 93
Inborn genetic diseasesTotal: 73
MPZ-related disorderTotal: 55
Charcot-Marie-Tooth disease dominant intermediate DTotal: 40
Dejerine-Sottas diseaseTotal: 32

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000530.8. 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
2
clinvar
3
clinvar
8
clinvar
65
clinvar
 78
missense
37
clinvar
94
clinvar
261
clinvar
9
clinvar
 401
nonsense
19
clinvar
6
clinvar
4
clinvar
 29
start loss
1
clinvar
 1
frameshift
30
clinvar
17
clinvar
15
clinvar
 62
splice donor/acceptor (+/-2bp)
7
clinvar
17
clinvar
4
clinvar
 28
Total96137292740599

Highest pathogenic variant AF is 0.000021690254

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000530.8RefSeqNP_000521.26MANE Select
ENST00000533357.5EnsemblENSP00000432943.16MANE Select
NM_001315491.2RefSeqNP_001302420.16Standard
ENST00000463290.5EnsemblENSP00000431538.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell adhesion molecules (CAMs) - Homo sapiens (human)
  • Neural Crest Differentiation

Biological Process

  • chemical synaptic transmission
  • myelination
  • negative regulation of apoptotic process
  • cell-cell adhesion via plasma-membrane adhesion molecules
  • cell aggregation

Molecular Function

  • structural molecule activity

Cellular Component

  • lysosome
  • rough endoplasmic reticulum
  • plasma membrane
  • integral component of plasma membrane
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000533357
Coding exons
6
Length
5238
Individuals with no LoFs
125741
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125748
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9871091420.7670.000007791594
Missense (PolyPhen)2242.1050.5225475
Synonymous1.084858.50.8200.00000342508
Loss of Function2.43312.20.2475.21e-7138

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Is an adhesion molecule necessary for normal myelination in the peripheral nervous system. It mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction. {ECO:0000269|PubMed:10545037, ECO:0000269|PubMed:18337304}.;
Disease
DISEASE: Charcot-Marie-Tooth disease 1B (CMT1B) [MIM:118200]: 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:10214757, ECO:0000269|PubMed:10545037, ECO:0000269|PubMed:10737979, ECO:0000269|PubMed:10965800, ECO:0000269|PubMed:11437164, ECO:0000269|PubMed:11438991, ECO:0000269|PubMed:11445635, ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:12207932, ECO:0000269|PubMed:12221176, ECO:0000269|PubMed:12402337, ECO:0000269|PubMed:12477701, ECO:0000269|PubMed:12497641, ECO:0000269|PubMed:12707985, ECO:0000269|PubMed:12845552, ECO:0000269|PubMed:14711881, ECO:0000269|PubMed:15036333, ECO:0000269|PubMed:16488608, ECO:0000269|PubMed:18337304, ECO:0000269|PubMed:7504284, ECO:0000269|PubMed:7505151, ECO:0000269|PubMed:7527371, ECO:0000269|PubMed:7530774, ECO:0000269|PubMed:7550231, ECO:0000269|PubMed:7688964, ECO:0000269|PubMed:7693129, ECO:0000269|PubMed:7693130, ECO:0000269|PubMed:7694726, ECO:0000269|PubMed:8664899, ECO:0000269|PubMed:8797476, ECO:0000269|PubMed:8816708, ECO:0000269|PubMed:8835320, ECO:0000269|PubMed:8844219, ECO:0000269|PubMed:8990016, ECO:0000269|PubMed:9187667, ECO:0000269|PubMed:9217235, ECO:0000269|PubMed:9452091, ECO:0000269|PubMed:9452099, ECO:0000269|PubMed:9633821, ECO:0000269|Ref.40}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2I (CMT2I) [MIM:607677]: A dominant axonal 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). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:12477701, ECO:0000269|PubMed:14638973, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:9595994}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2J (CMT2J) [MIM:607736]: A dominant axonal 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). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Charcot-Marie-Tooth disease type 2J is characterized by the association of axonal peripheral neuropathy with hearing loss and pupillary abnormalities such as Adie pupil. {ECO:0000269|PubMed:10071056, ECO:0000269|PubMed:11080237, ECO:0000269|PubMed:15326256, ECO:0000269|PubMed:16775239}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Adie pupil (ADIEP) [MIM:103100]: A stationary, benign disorder characterized by tonic, sluggishly reacting pupil and hypoactive or absent tendon reflexes. Adie pupil is a characteristic of Charcot-Marie-Tooth disease type 2J. {ECO:0000269|PubMed:16775239}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type, D (CMTDID) [MIM:607791]: A 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. The dominant intermediate type D is characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:10406984}. Note=The disease may be 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:11438991, ECO:0000269|PubMed:11596785, ECO:0000269|PubMed:11835375, ECO:0000269|PubMed:12497641, ECO:0000269|PubMed:7506095, ECO:0000269|PubMed:8630052, ECO:0000269|PubMed:8816708, ECO:0000269|PubMed:9187667, ECO:0000269|PubMed:9222756, ECO:0000269|PubMed:9452055, ECO:0000269|PubMed:9452091, ECO:0000269|PubMed:9633821}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neuropathy, congenital hypomyelinating or amyelinating (CHN) [MIM:605253]: A severe degenerating neuropathy that results from a congenital impairment in myelin formation. It is clinically characterized by early onset of hypotonia, areflexia, distal muscle weakness, and very slow nerve conduction velocities (as low as 3m/s). Some patients manifest nearly complete absence of spontaneous limb movements, respiratory distress at birth, and complete absence of myelin shown by electron microscopy of peripheral nerves. Inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:15184631}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Roussy-Levy syndrome (ROULS) [MIM:180800]: Autosomal dominant disorder that resembles Charcot-Marie-Tooth disease type 1 in that it presents with foot deformity, weakness and atrophy of distal limb muscles, especially the peronei, and absent tendon reflexes. The phenotype differs, however, in that it includes static tremor of the upper limbs and gait ataxia. {ECO:0000269|PubMed:10553995}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0931

Intolerance Scores

LoFtool
0.157
RVIS EVS
-0.21
RVIS percentile EVS
38.28

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.621

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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