MPZ

Chr 1ADAR

myelin protein zero

Also known as: CMT1, CMT1B, CMT2I, CMT2J, CMT4E, CMTDI3, CMTDID, DSS

NCBI Gene: 4359 ENSG00000158887 UniProt: P25189 OMIM: 159440

The encoded protein is a major structural glycoprotein of peripheral myelin that forms and stabilizes the compact myelin sheath in Schwann cells. Mutations cause a spectrum of autosomal dominant and recessive peripheral neuropathies including Charcot-Marie-Tooth disease types 1B and 2I/2J, Dejerine-Sottas disease, congenital hypomyelinating neuropathy, and Roussy-Levy syndrome. The pathogenic mechanism involves dominant-negative effects that disrupt normal myelin formation and maintenance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.647 OMIM phenotypes

Clinical Summary— MPZ

🧬

Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

📋

ClinVar Variants

135 unique Pathogenic / Likely Pathogenic· 299 VUS of 573 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — MPZ

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.272

Z-score 2.43

OE 0.25 (0.11–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.99Z-score

OE missense 0.77 (0.66–0.90)

109 obs / 142.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.11–0.64)

0≤0.351.4

Missense OE?0.77 (0.66–0.90)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 3 / 12.2Missense obs/exp: 109 / 142.1Syn Z: 1.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMPZ-related neuropathy, congenital hypomyelinatingOTHERAD

This gene — mechanism propensity

0.7230th %ile

GOF

0.6833th %ile

LOF

0.3941th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

LOF1 literature citation · 57% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe two early-onset mutations caused two distinct abnormalities. H52R was correctly glycosylated and trafficked to the plasma membrane, but strongly affected intercellular adhesion. When co-expressed with wild-type MPZ (wtMPZ), a functional dominant negative effect was observed.1

GOFMPZ mutations cause neuropathy gain of function mechanisms that are largely independent MPZs normal role of mediating myelin compaction.2

LOFLoss of function MPZ mutation causes milder CMT1B neuropathy.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

573 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73

Likely Pathogenic62

VUS299

Likely Benign98

Benign8

Conflicting31

Pathogenic

Likely Pathogenic

299

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	49	19	4	1	73
Likely Pathogenic	28	32	1	1	62
VUS	23	245	23	8	299
Likely Benign	0	4	35	59	98
Benign	0	0	8	0	8
Conflicting	—				31
Total	100	300	71	69	571

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap MPZ — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →