GeneBe

PLP1

protein-coding

proteolipid protein 1

Gene summary

This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]

Previous symbols:
  • SPG2
  • PLP

MANE transcript

NM_000533.5

Inheritance

XL

ClinVar variants

P:184U:155B:69

Top phenotype

Spastic paraplegia 2, X-linked; Pelizaeus-Merzbacher disease

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:103,773,718-103,792,619

External References & Databases

Ensembl (ENSG00000123560)NCBI Gene (5354)OMIM (300401)HGNC:9086GenCCUniProt (P60201)AlphaFoldClinVar (PLP1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~18.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 2MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010733

Submitter: Ambry Genetics

Pelizaeus-Merzbacher spectrum disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010714

Submitter: Ambry Genetics

Pelizaeus-Merzbacher disease, transitional formSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017223

Submitter: Orphanet

Pelizaeus-Merzbacher disease, classic formSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017222

Submitter: Orphanet

Pelizaeus-Merzbacher disease in female carriersSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017224

Submitter: Orphanet

null syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017225

Submitter: Orphanet

Pelizaeus-Merzbacher disease, connatal formSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017221

Submitter: Orphanet

Pelizaeus-Merzbacher spectrum disorderSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010714

Submitter: Labcorp Genetics (formerly Invitae)

Pelizaeus-Merzbacher spectrum disorderSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010714

Submitter: PanelApp Australia

hereditary spastic paraplegia 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010733

Submitter: G2P

hereditary spastic paraplegia 2SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010733

Submitter: Orphanet

Pelizaeus-Merzbacher spectrum disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010714

Submitter: G2P

Pelizaeus-Merzbacher spectrum disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010714

Submitter: ClinGen

*PLP1* has been reported in relation to both X-linked Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegia (SPG). Evidence suggests that these disorders are at different ends of the same clinical spectrum; the curation presented here is specifically for the more severe Pelizaeus-Merzbacher presentation. The *PLP1* gene encodes two major alternatively spliced transcripts: a full-length transcript that encodes PLP, and a transcript lacking the PLP specific domain in exon 3, known as DM20. Differing molecular mechanisms are known to cause these disorders, including overexpression of PLP/DM20 (commonly caused by large, multi-gene duplications including *PLP1* and resulting in "classic" PMD); missense variants resulting in misfolding of both PLP and DM20 (resulting in the more severe, "connatal" PMD); null variants (resulting in milder presentations of PMD or "complicated" SPG); and milder misfolding variants (often associated with the SPG phenotype). Note that though duplications are the most common mechanism of PMD, none are curated here, as most involve more genes than just *PLP1*. Though extensive functional evidence (including additional animal models) is available to support the link between *PLP1* and PMD, only a subset is presented here. In summary, there is definitive evidence supporting the relationship between *PLP1* and X-linked Pelizaeus-Merzbacher disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 7, 2018 (SOP Version 5).

hereditary spastic paraplegia 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010733

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spastic paraplegia 2, X-linked; Pelizaeus-Merzbacher diseaseXL

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 2479017; 2773936; 7539211; 8659540; 8696336; 10210128; 10417279; 11093273; 11761472; 15627202; 16130097; 16157902; 16374829; 16778599; 17438221; 17568416; 18190592; 19396823; 20513814; 20660364; 21623770; 22422208; 27882623; 29478609; 29486744Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLP1 variants in ClinVar

16 Conditions Cataloged
Hereditary spastic paraplegia 2Total: 233
Pelizaeus-Merzbacher diseaseTotal: 167
not providedTotal: 123
Inborn genetic diseasesTotal: 27
PLP1-related disorderTotal: 26
not specifiedTotal: 19
Hereditary spastic paraplegiaTotal: 4
Pelizaeus-Merzbacher disease, atypicalTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000533.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
8
clinvar
58
clinvar
5
clinvar
 75
missense
13
clinvar
78
clinvar
141
clinvar
4
clinvar
2
clinvar
 238
nonsense
14
clinvar
11
clinvar
 25
start loss
6
clinvar
 6
frameshift
18
clinvar
19
clinvar
2
clinvar
 39
splice donor/acceptor (+/-2bp)
12
clinvar
9
clinvar
4
clinvar
 25
Total63121155627408

Highest pathogenic variant AF is 0.0000036449226

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000533.5RefSeqNP_000524.37MANE Select
ENST00000621218.5EnsemblENSP00000484450.17MANE Select
NM_001128834.3RefSeqNP_001122306.17Standard
NM_001305004.1RefSeqNP_001291933.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glial Cell Differentiation
  • Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways

Biological Process

  • inflammatory response
  • integrin-mediated signaling pathway
  • chemical synaptic transmission
  • axon ensheathment
  • glial cell differentiation

Molecular Function

  • structural molecule activity
  • protein binding
  • structural constituent of myelin sheath

Cellular Component

  • plasma membrane
  • integral component of membrane
  • myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000418604
Coding exons
7
Length
18902
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.04451030.4360.000007551791
Missense (PolyPhen)1747.8870.355856
Synonymous-0.1374442.91.030.00000349570
Loss of Function2.6908.420.005.34e-7161

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: This is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin.;
Disease
DISEASE: Leukodystrophy, hypomyelinating, 1 (HLD1) [MIM:312080]: A X-linked recessive disorder of the central nervous system in which myelin is not formed properly. Clinically characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. {ECO:0000269|PubMed:10417279, ECO:0000269|PubMed:10425042, ECO:0000269|PubMed:11093273, ECO:0000269|PubMed:11786921, ECO:0000269|PubMed:1376966, ECO:0000269|PubMed:1384324, ECO:0000269|PubMed:15712223, ECO:0000269|PubMed:1707231, ECO:0000269|PubMed:1708672, ECO:0000269|PubMed:1715570, ECO:0000269|PubMed:2479017, ECO:0000269|PubMed:2480601, ECO:0000269|PubMed:2773936, ECO:0000269|PubMed:7531827, ECO:0000269|PubMed:7539213, ECO:0000269|PubMed:7541731, ECO:0000269|PubMed:7573159, ECO:0000269|PubMed:7679906, ECO:0000269|PubMed:7683951, ECO:0000269|PubMed:7684886, ECO:0000269|PubMed:8037216, ECO:0000269|PubMed:8909455, ECO:0000269|PubMed:9008538, ECO:0000269|PubMed:9143933, ECO:0000269|PubMed:9482656, ECO:0000269|PubMed:9633722, ECO:0000269|PubMed:9747038, ECO:0000269|PubMed:9788732, ECO:0000269|PubMed:9894878, ECO:0000269|PubMed:9934976}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 2, X-linked (SPG2) [MIM:312920]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG2 is characterized by spastic gait and hyperreflexia. In some patients, complicating features include nystagmus, dysarthria, sensory disturbance, mental retardation, optic atrophy. {ECO:0000269|PubMed:10319897, ECO:0000269|PubMed:11093273, ECO:0000269|PubMed:15450775, ECO:0000269|PubMed:17438221, ECO:0000269|PubMed:24103481, ECO:0000269|PubMed:7522741, ECO:0000269|PubMed:8012387, ECO:0000269|PubMed:8780101, ECO:0000269|PubMed:8956049, ECO:0000269|PubMed:9489796}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.368

Intolerance Scores

RVIS EVS
0.01
RVIS percentile EVS
54.63

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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