PMP22

Chr 17ADAR

peripheral myelin protein 22

Also known as: CIDP, CMT1A, CMT1E, DSS, GAS-3, GAS3, HMSNIA, HNPP

NCBI Gene: 5376 ENSG00000109099 UniProt: Q9NR77 OMIM: 601097

This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Mutations cause several inherited peripheral neuropathies including Charcot-Marie-Tooth disease types 1A and 1E, Dejerine-Sottas disease, hereditary neuropathy with liability to pressure palsies, and Roussy-Levy syndrome, with inheritance patterns that are primarily autosomal dominant but can be autosomal recessive. The pathogenic mechanism involves disruption of peripheral myelin structure and function due to altered PMP22 protein levels or function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.396 OMIM phenotypes

Clinical Summary— PMP22

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 1A · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PMP22

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.39LOEUF

pLI 0.910

Z-score 2.58

OE 0.00 (0.00–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

0.42Z-score

OE missense 0.88 (0.73–1.06)

79 obs / 90.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.39)

0≤0.351.4

Missense OE0.88 (0.73–1.06)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

LoF obs/exp: 0 / 7.7Missense obs/exp: 79 / 90.1Syn Z: -0.28

0.4190th %ile

GOF

0.6932th %ile

LOF

0.4825th %ile

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

GOFprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.39

DN1 literature citation

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

DNUnlike CMT associated with the PMP22 duplication and a gene-dosage effect, the Ala67Pro mutation is likely to cause a dominant-negative effect, like the majority of DSS and CMT point mutations.PMID:10330345

GOFThis study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype, possibly through a toxic gain-of-function mechanism.PMID:28748849

LOFHNPP is in the majority of cases correlated with heterozygous deletion of the whole PMP22 gene or other mutations leading to functional haploinsufficiency.PMID:25265422

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