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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

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 →

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 OE?0.00 (0.00–0.39)

0≤0.351.4

Missense OE?0.88 (0.73–1.06)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

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

This gene — mechanism propensity

0.4190th %ile

GOF

0.6932th %ile

LOF

0.4825th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.39 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median · 1 literature citation

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.1

GOFThis study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype, possibly through a toxic gain-of-function mechanism.2

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