MPZ

Chr 1ADAR

myelin protein zero

Also known as: CHM, CHN2, CMT1, CMT1B, CMT2I, CMT2J, CMT4E, CMTDI3

NCBI Gene: 4359 ENSG00000158887 UniProt: P25189

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]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, dominant intermediate DMIM #607791

Charcot-Marie-Tooth disease, type 1BMIM #118200

Charcot-Marie-Tooth disease, type 2IMIM #607677

Charcot-Marie-Tooth disease, type 2JMIM #607736

Dejerine-Sottas diseaseMIM #145900

ADAR

Hypomyelinating neuropathy, congenital, 2MIM #618184

Roussy-Levy syndromeMIM #180800

UniProtAdie pupil

UniProtDejerine-Sottas syndrome

549

ClinVar variants

162

Pathogenic / LP

0.27

pLI score

Active trials

Clinical Summary— MPZ

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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.

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ClinVar Variants

162 Pathogenic / Likely Pathogenic· 240 VUS of 549 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.64LOEUF

pLI 0.272

Z-score 2.43

OE 0.25 (0.11–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.99Z-score

OE missense 0.77 (0.66–0.90)

109 obs / 142.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.25 (0.11–0.64)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.66–0.90)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82

0≤1.21.6

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

ClinVar Variant Classifications

549 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic88

Likely Pathogenic74

VUS240

Likely Benign97

Benign7

Conflicting43

Pathogenic

Likely Pathogenic

240

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	28	30	1	88
Likely Pathogenic	21	39	12	2	74
VUS	6	188	39	7	240
Likely Benign	0	4	35	58	97
Benign	0	0	6	1	7
Conflicting	—				43
Total	56	259	122	69	549

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

View in ClinVar →

Protein Context — Lollipop Plot

MPZ · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MPZ-related neuropathy, congenital hypomyelinating

definitive

ADUndeterminedUncertain

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

MYELIN PROTEIN ZERO; MPZ

MIM #159440 · *

Charcot-Marie-Tooth disease, dominant intermediate D

MIM #607791