Incidental Mutation 'R0025:Pmp22'
ID15123
Institutional Source Beutler Lab
Gene Symbol Pmp22
Ensembl Gene ENSMUSG00000018217
Gene Nameperipheral myelin protein 22
SynonymsGas-3
MMRRC Submission 038320-MU
Accession Numbers

Ncbi RefSeq: NM_008885.2; MGI:97631

Is this an essential gene? Possibly essential (E-score: 0.625) question?
Stock #R0025 (G1)
Quality Score
Status Validated
Chromosome11
Chromosomal Location63128982-63159547 bp(+) (GRCm38)
Type of Mutationcritical splice acceptor site
DNA Base Change (assembly) A to T at 63158250 bp
ZygosityHeterozygous
Amino Acid Change
Ref Sequence ENSEMBL: ENSMUSP00000104342 (fasta)
Gene Model predicted gene model for transcript(s): [ENSMUST00000018361] [ENSMUST00000018361] [ENSMUST00000108700] [ENSMUST00000108700] [ENSMUST00000108701] [ENSMUST00000108701] [ENSMUST00000108702] [ENSMUST00000108702]
Predicted Effect probably null
Transcript: ENSMUST00000018361
SMART Domains Protein: ENSMUSP00000018361
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000018361
SMART Domains Protein: ENSMUSP00000018361
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108700
SMART Domains Protein: ENSMUSP00000104340
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108700
SMART Domains Protein: ENSMUSP00000104340
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108701
SMART Domains Protein: ENSMUSP00000104341
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.7e-50 PFAM
Pfam:Claudin_2 55 155 1.2e-10 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108701
SMART Domains Protein: ENSMUSP00000104341
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.7e-50 PFAM
Pfam:Claudin_2 55 155 1.2e-10 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108702
SMART Domains Protein: ENSMUSP00000104342
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Predicted Effect probably null
Transcript: ENSMUST00000108702
SMART Domains Protein: ENSMUSP00000104342
Gene: ENSMUSG00000018217

DomainStartEndE-ValueType
Pfam:PMP22_Claudin 1 153 5.8e-50 PFAM
Pfam:Claudin_2 13 155 1.1e-12 PFAM
Meta Mutation Damage Score 0.48 question?
Coding Region Coverage
  • 1x: 75.6%
  • 3x: 62.5%
  • 10x: 33.3%
  • 20x: 15.9%
Validation Efficiency 95% (69/73)
MGI Phenotype Strain: 2447704; 3614822
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] 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]
PHENOTYPE: Mice with one or two copies of several mutations exhibit tremors, a tendency toward seizures, and partial paralysis associated with demyelination and loss of peripheral axons. Mutants have high juvenile mortality and males are often sterile. [provided by MGI curators]
Allele List at MGI

All alleles(11) : Targeted(4) Spontaneous(3) Chemically induced(4)

Other mutations in this stock
Total: 40 list
GeneRefVarChr/LocMutationPredicted EffectZygosity
Acsm1 A T 7: 119,658,315 T435S probably damaging Het
Agtpbp1 G A 13: 59,500,200 T602I probably benign Het
Ahnak2 T A 12: 112,785,534 D231V probably damaging Het
Ampd3 G A 7: 110,793,669 D215N probably benign Het
Ate1 A G 7: 130,503,793 S332P probably damaging Het
Ces1f T C 8: 93,271,885 E161G probably benign Het
Ces2g A G 8: 104,965,996 probably benign Het
Cntnap4 T G 8: 112,803,164 L668R probably damaging Het
Col1a2 G A 6: 4,518,822 probably benign Het
Csf1 A G 3: 107,748,644 V245A probably benign Het
Ctss A G 3: 95,550,137 Y302C probably damaging Het
Dbt C T 3: 116,534,783 H158Y probably benign Het
Dennd6b T C 15: 89,186,183 I428V probably benign Het
Dnah9 G A 11: 65,969,955 probably benign Het
Dock3 G T 9: 106,913,268 Q1419K possibly damaging Het
Enpp6 A G 8: 47,066,000 K268E probably damaging Het
Eps15l1 T G 8: 72,381,497 probably benign Het
Gm10800 C A 2: 98,666,580 M209I probably benign Het
Herc3 C T 6: 58,874,308 P514L probably damaging Het
Mark2 T C 19: 7,285,922 D160G probably damaging Het
Mbd4 A G 6: 115,844,568 probably null Het
Mink1 T C 11: 70,613,042 W1263R probably damaging Het
Nlrp14 A T 7: 107,181,258 probably benign Het
Osbp T C 19: 11,983,958 Y454H probably damaging Het
Pak7 T C 2: 136,100,784 K479E possibly damaging Het
Pard3 C A 8: 127,161,308 D73E probably damaging Het
Scn4a C T 11: 106,324,560 V1197I probably benign Het
Slc36a2 A G 11: 55,162,795 L339P probably damaging Het
Smg1 G A 7: 118,212,443 T104I possibly damaging Het
Stx18 T A 5: 38,092,564 Y74N probably damaging Het
Stxbp5 A T 10: 9,762,748 H1102Q probably damaging Het
Tom1l2 T C 11: 60,230,134 K450E probably damaging Het
Tpo T C 12: 30,100,390 Q497R probably benign Het
Tsc2 A G 17: 24,631,004 probably benign Het
Vit G A 17: 78,599,835 G229R probably benign Het
Vwf T A 6: 125,682,812 I2658N probably benign Het
Wdr36 T A 18: 32,859,307 D632E probably damaging Het
Zcchc6 A T 13: 59,805,328 D99E probably benign Het
Zfp654 A G 16: 64,784,818 V466A probably benign Het
Zfp941 T C 7: 140,813,272 D58G probably benign Het
Other mutations in Pmp22
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL01780:Pmp22 APN 11 63158308 missense probably benign
IGL02350:Pmp22 APN 11 63158308 missense probably benign
IGL02357:Pmp22 APN 11 63158308 missense probably benign
IGL02423:Pmp22 APN 11 63158292 missense possibly damaging 0.94
IGL03107:Pmp22 APN 11 63158309 missense probably benign
PIT4431001:Pmp22 UTSW 11 63151241 missense probably benign 0.00
R0025:Pmp22 UTSW 11 63158250 critical splice acceptor site probably null
R0453:Pmp22 UTSW 11 63151103 intron probably benign
R0561:Pmp22 UTSW 11 63134424 missense probably damaging 1.00
R3858:Pmp22 UTSW 11 63134475 missense probably benign 0.00
R5107:Pmp22 UTSW 11 63158411 missense probably damaging 0.99
R6573:Pmp22 UTSW 11 63158273 missense probably damaging 1.00
R6574:Pmp22 UTSW 11 63158273 missense probably damaging 1.00
R6575:Pmp22 UTSW 11 63158273 missense probably damaging 1.00
Protein Function and Prediction

PMP22 is a 22-kD protein component of myelin in the peripheral nervous system (1). Mutations in Pmp22 disrupt the organization of myelin and axonal integrity [reviewed in (2)]. PMP22 expression increases in starvation states indicating that PMP22 may function in cell survival and/or proliferation (3).

Expression/Localization

PMP22 is mainly produced by myelinating Schwann cells of the peripheral nerves and expressed in the compact portion of essentially all myelinated fibers in the peripheral nervous system (1;4;5). PMP22 transcripts are expressed diffusely at embryonic stages and are detectable at low levels in some non-neuronal tissues [reviewed in (2)].  PMP22 is low in the central nervous system with expression observed in a rostral-caudal pattern: cranial nuclei express during embryonic stages; spinal motor neurons after birth [(5;6); reviewed in (2)]. In humans, different PMP22 transcripts exhibit distinct distribution in tissues (5;6).

Background

Table 1. Human phenotypes associated with PMP22 mutations.

Phenotype

OMIM #

Brief Description

Refs

Charcot-Marie-Tooth disease, type 1A

118220

A sensorineural peripheral polyneuropathy; slowly progressive weakness and atrophy of the distal limb muscles usually beginning in the legs and feet. In CMT1E mild deafness may also occur.

(7;8)

Charcot-Marie-Tooth disease, type 1E

118300

(9;10)

Dejerine-Sottas disease

145900

Demyelinating peripheral neuropathy with onset in infancy; affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia.

(11;12)

Neuropathy, inflammatory demyelinating

139393

An acute inflammatory demyelinating polyneuropathy characterized most commonly by symmetric limb weakness and loss of tendon reflexes

(13)

Neuropathy, recurrent, with pressure palsies

162500

Peroneal muscle weakness; radial, ulnar, and median nerve muscles may be affected

(12;14)

Roussy-Levy syndrome

180800

This disorder usually begins in infancy or childhood and manifests as a delay in starting to walk with clumsiness and frequent falls. Affected individuals can also have foot deformity, weakness and atrophy of distal limb muscles, especially the peronei, absent tendon reflexes, decreased excitability of muscles to galvanic and faradic stimulation, static tremor, gait ataxia, and some distal sensory loss.

(15)

 

Mice with one or two copies of several mutations exhibit tremors, a tendency toward seizures, and partial paralysis associated with demyelination and loss of peripheral axons. Mutants have high juvenile mortality and males are often sterile.

 

Pmp22tm1Ueli/tm1Ueli; MGI:2447704

involves: 129S/SvEv

Homozygotes exhibit convulsive seizures, progressive hindlimb paralysis, abnormal axon and myelin sheath morphology, abnormal myelination, and abnormal action potentials (16).

 

Pmp22tm1Ueli/tm1Ueli; MGI:2447704

involves: 129S/SvEv * C57BL/6

In this genetic background, homozygotes display increased Schwann cell density, proliferation, and apoptosis as well as hypermyelination (17).

 

­­­­­­­

Pmp22tm1Lnot/tm1Lnot; MGI:3614822

Not Specified

Homozygotes exhibit Schwann cells arrested at the promyelinating stage, abnormal neuron morphology, decreases in axon diameter, demyelination, tremors, hindlimb paralysis, and an impaired ability to mate (18).

References
Posted On2012-12-12
Science WriterAnne Murray