PLP1

Summary

PLP1 (proteolipid protein 1, HGNC:9086) is a protein-coding gene on chromosome Xq22.2, encoding Myelin proteolipid protein (P60201). This is the major myelin protein from the central nervous system. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 5354 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Pelizaeus-Merzbacher spectrum disorder (Definitive, ClinGen) — +6 more curated relationships
• Clinical variants (ClinVar): 406 total — 64 pathogenic, 90 likely-pathogenic
• Phenotypes (HPO): 128
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity sufficient evidence
• MANE Select transcript: NM_000533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9086
Approved symbol	PLP1
Name	proteolipid protein 1
Location	Xq22.2
Locus type	gene with protein product
Status	Approved
Aliases	GPM6C
Ensembl gene	ENSG00000123560
Ensembl biotype	protein_coding
OMIM	300401
Entrez	5354

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 28 protein_coding, 10 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000422393, ENST00000433491, ENST00000434483, ENST00000443502, ENST00000455268, ENST00000461231, ENST00000464776, ENST00000465975, ENST00000466486, ENST00000476160, ENST00000478642, ENST00000479569, ENST00000480325, ENST00000485688, ENST00000485931, ENST00000494119, ENST00000494475, ENST00000495678, ENST00000496836, ENST00000612423, ENST00000619236, ENST00000619257, ENST00000621218, ENST00000867697, ENST00000867698, ENST00000867699, ENST00000867700, ENST00000867701, ENST00000867702, ENST00000867703, ENST00000867704, ENST00000867705, ENST00000867706, ENST00000867707, ENST00000867708, ENST00000867709, ENST00000867710, ENST00000867711, ENST00000867712, ENST00000920048, ENST00000920049, ENST00000951435

RefSeq mRNA: 4 — MANE Select: NM_000533 NM_000533, NM_001128834, NM_001305004, NM_199478

CCDS: CCDS14513, CCDS14514

Canonical transcript exons

ENST00000621218 — 7 exons

Exon	Start	End
ENSE00003675028	103785582	103785768
ENSE00003722507	103787798	103787966
ENSE00003734574	103786465	103786726
ENSE00003745114	103789333	103789398
ENSE00003745965	103790527	103792619
ENSE00003749941	103788437	103788510
ENSE00003844824	103776840	103776999

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 153.7198 / max 13785.6349, expressed in 410 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197054	56.5882	375
197057	49.5172	256
197055	29.1097	311
197056	7.9902	174
197065	2.3887	171
197071	1.9273	151
197072	1.1118	127
197061	0.9803	113
197076	0.7290	92
197066	0.4355	76

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	99.99	gold quality
middle frontal gyrus	UBERON:0002702	99.99	gold quality
inferior vagus X ganglion	UBERON:0005363	99.99	gold quality
pons	UBERON:0000988	99.98	gold quality
subthalamic nucleus	UBERON:0001906	99.98	gold quality
superior vestibular nucleus	UBERON:0007227	99.98	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.97	gold quality
ventral tegmental area	UBERON:0002691	99.97	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.96	gold quality
spinal cord	UBERON:0002240	99.96	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.96	gold quality
cranial nerve II	UBERON:0000941	99.95	gold quality
lateral globus pallidus	UBERON:0002476	99.95	gold quality
substantia nigra pars compacta	UBERON:0001965	99.94	gold quality
medulla oblongata	UBERON:0001896	99.92	gold quality
midbrain	UBERON:0001891	99.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.91	gold quality
substantia nigra	UBERON:0002038	99.90	gold quality
frontal pole	UBERON:0002795	99.90	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.90	gold quality
putamen	UBERON:0001874	99.88	gold quality
globus pallidus	UBERON:0001875	99.87	gold quality
amygdala	UBERON:0001876	99.85	gold quality
medial globus pallidus	UBERON:0002477	99.85	gold quality
caudate nucleus	UBERON:0001873	99.83	gold quality
parietal lobe	UBERON:0001872	99.81	gold quality
postcentral gyrus	UBERON:0002581	99.79	gold quality
olfactory bulb	UBERON:0002264	99.78	gold quality
hypothalamus	UBERON:0001898	99.77	gold quality
trigeminal ganglion	UBERON:0001675	99.76	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	23864.93
E-HCAD-25	yes	12232.31
E-GEOD-180759	yes	8776.63
E-HCAD-30	yes	7287.03
E-HCAD-35	yes	6154.87
E-MTAB-8221	yes	2637.80
E-HCAD-5	yes	2365.95
E-MTAB-10485	yes	1176.11
E-GEOD-98556	yes	1104.02
E-CURD-126	yes	877.52
E-MTAB-9906	yes	765.40
E-HCAD-56	yes	585.03
E-ANND-5	yes	491.51
E-GEOD-124472	yes	469.79
E-MTAB-10018	yes	404.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SIRT2	Activation

Upstream regulators (CollecTRI, top): IRF6, MYT1, NEUROG3, NKX2-2, NKX6-2, OLIG1, PPARD, SOX10, SP1, YY1

miRNA regulators (miRDB)

150 targeting PLP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 3 (sufficient evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• PLP1 deletions are likely caused by nonhomologous end joining (PMID:12297985)
• A PLP splicing abnormality is associated with an unusual presentation of PMD. (PMID:12325077)
• a study of the mutations in Pelizaeus Merzbacher disease. (PMID:12491939)
• Decreased expression of a number of myelin-related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP) was noted in nucleus accumbens of cocaine abusers (PMID:15009677)
• A Korean boy diagnosed with SPG2 caused by a mutation that results in a Pro215Leu substitution in the second extracellular domain. (PMID:15450775)
• Mutations are associated with Pelizaeus-Merzbacher disease and spastic paraplegia type 2. (review) (PMID:15627202)
• the genetic polymorphisms within PLP1 in male are likely to confer an increased susceptibility to schizophrenia in the Chinese population. (PMID:15694262)
• 17 new sequence variants resulting in truncation, AA substitution or splice consensus sequence changes were found. 7 are in the transmembrane domain and affect folding. (PMID:15712223)
• premature oligomerization of PLP in the endoplasmic reticulum of oligodendrocytes contributes to the pathology of Pelizaeus-Merzbacher disease (PMID:15753308)
• Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA. (PMID:15837131)
• Sequencing of the proteolipid protein 1 gene showed a novel mutation, Leu30Arg (c.89TG) in primary progressive multiple sclerosis. (PMID:16130097)
• The observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing. (PMID:16287154)
• Electrodiagnostic studies and a sural nerve biopsy showed features of a dystrophic axonal neuropathy. Molecular studies identified a small duplication downstream of PLP1. (PMID:16374829)
• Genomic structures of X-chromosome segmental duplications of the PLP1 gene reveal highly variable distal breakpoints clustered around low-copy repeats. Such tandem duplications form by a coupled homologous and nonhomologous recombination mechanism. (PMID:16380909)
• PLP1 duplication may be stimulated by flanking low-copy repeats, possibly non-homologous pairs at both the proximal and distal breakpoints, and supports an alternative role of genomic architecture in rearrangements responsible for genomic disorders (PMID:16774974)
• Function of a novel mutagenized heptapeptide has significant impact on pathogenesis and provides new insight into the functions of the two splice isoforms encoded by the PLP1 gene. (PMID:17171701)
• This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS. (PMID:17438221)
• Covalent protein cross-links emerge as a cause, rather than as a consequence, of endoplasmic reticulum retention in Pelizaeus-Merzbacher disease. (PMID:17962415)
• Five Pelizaeus-Merzbacher disease (PMD) male patients affected by the classic PMD form carrying a PLP1 gene duplication. (PMID:18190592)
• the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy (PMID:18437021)
• Study found that various PLP1 mutations result in missplicing, including a missense in exon 2 and a nucleotide substitution in intron 3 outside the donor and acceptor splicing sites in Pelizaeus-Merzbacher disease and spastic paraplegia patients. (PMID:18470932)
• Transgenic mice overexpressing proteolipid protein develop a low-grade chronic inflammatory disease of the central nervous system white matter tracts with an increase in both CD8-positive T-lymphocytes and CD11b-positive macrophage-like cells. (PMID:18555697)
• No association between the oligodendrocyte-related gene PLP1 and schizophrenia. (PMID:18604471)
• genomic duplications and one missense mutation (p. P173S) of the PLP1 gene in eight Chinese patients with Pelizaeus-Merzbacher disease (PMD). (PMID:19024090)
• Variable clinical expression of Pelizaeus-Merzbacher disease was seen in 5 members of a family bearing a novel missense mutation in proteolipid protein 1, c.619T>C. (PMID:19151366)
• hnRNPH and F regulate DM20 splicing by recruiting U1snRNP and hnRNPH plays a primary role in DM20 splice site selection in vivo (PMID:19244236)
• his study presented new mutation and variable sizes of duplications in patient with Pelizaeus-Merzbacher disease. (PMID:19328639)
• PLP1 gene duplication seems to result both in overexpression and in a shift of the PLP/DM20 splicing balance in direction of the PLP isoform. (PMID:19376225)
• A missense mutation (p.D57Y) was found in the PLP1 gene; thus, it appears that the Arena syndrome is, in fact, Pelizaeus-Merzbacher disease. (PMID:19396823)
• The patterns of neuronal loss in Pelizaeus-Merzbacher disease appear to be dependent on the type of mutation (e.g. duplication, complete gene deletion, missense or exon-skipping) affecting proteolipid protein 1. (PMID:19562355)
• A242V PLP1 mutant, which causes severe Pelizaeus-Merzbacher disease, was more stable and accumulated at the endoplasmic-reticulum. (PMID:19825935)
• PLP1 gene mutations cause hereditary spastic paraplegia. (PMID:19955111)
• These results suggest for the first time that PLP may have functions in humans not only in oligodendrocytes but also in neurons and could be implicated in axono-glial communication (PMID:20036320)
• report on a family of two young boys and their mother who share the same unusual 4-bp deletion of the PLP1 gene: c51_54 del TTCC, causing truncation of the PLP1 in exon 2. The brain MRI appearances in this unique deletion, using MR imaging, are described. (PMID:20186781)
• Central nervous system myelination is compromised by overexpression of proteolipid protein PLP/DM20 in a transgenic mouse model of Pelizaeus-Merzbacher disease. (PMID:20629189)
• Inflammation in mammals with increased Plp1 gene dosage may also contribute to axonal degeneration described in patients and transgenic rodents with PLP1 increased gene dosage. (PMID:20885931)
• A patient with Pelizaeus-Merzbacher disease has duplication of all 7 exons of the PLP1 gene. This duplication was inherited from the patient’s mother, who is an unaffected carrier of the mutation. (PMID:21082496)
• G Run-mediated recognition of proteolipid protein and DM20 5’ splice sites by U1 small nuclear RNA is regulated by context and proximity to the splice site. (PMID:21127064)
• Data suggest that a defective disulfide bond in proteolipid protein 1 could be important in the pathogenesis of Pelizaeus-Merzbacher disease. (PMID:21177054)
• Results prove for the first time the interaction of PLP and MAL2 in oligodendrocytic cells, supporting the transcytotic model of PLP transport previously suggested. (PMID:21573057)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	plp1b	ENSDARG00000011929
danio_rerio	plp1a	ENSDARG00000103732
mus_musculus	Plp1	ENSMUSG00000031425
rattus_norvegicus	Plp1	ENSRNOG00000002419
drosophila_melanogaster	M6	FBGN0037092
caenorhabditis_elegans		WBGENE00017437

Paralogs (2): GPM6B (ENSG00000046653), GPM6A (ENSG00000150625)

Protein

Protein identifiers

Myelin proteolipid protein — P60201 (reviewed: P60201)

Alternative names: Lipophilin

All UniProt accessions (9): A0A0S2Z4D4, A8K9L3, B1B1G1, B1B1G2, B1B1G3, B1B1G4, B1B1G6, B4DI30, P60201

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with MAL.

Subcellular location. Cell membrane. Myelin membrane.

Disease relevance. Leukodystrophy, hypomyelinating, 1 (HLD1) [MIM:312080] An 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. The disease is caused by variants affecting the gene represented in this entry. 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, intellectual disability, optic atrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the myelin proteolipid protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
P60201-1	1	yes
P60201-2	DM-20

RefSeq proteins (4): NP_000524, NP_001122306, NP_001291933, NP_955772 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001614	Myelin_PLP	Family
IPR018237	Myelin_PLP_CS	Conserved_site

Pfam: PF01275

UniProt features (101 total): sequence variant 74, lipid moiety-binding region 7, topological domain 5, transmembrane region 4, sequence conflict 3, modified residue 3, disulfide bond 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2XPG	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60201-F1	77.81	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 114, 116, 118, 6, 7, 10, 109, 139, 141, 199

Disulfide bonds (2): 184–228, 201–220

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 413 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, BENPORATH_ES_WITH_H3K27ME3, GOBP_INFLAMMATORY_RESPONSE, KAAB_FAILED_HEART_ATRIUM_DN, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_GLIAL_CELL_DEVELOPMENT, GCAAGGA_MIR502, GOBP_NEUROGENESIS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_CELL_CELL_SIGNALING

GO Biological Process (10): inflammatory response (GO:0006954), chemical synaptic transmission (GO:0007268), axon ensheathment (GO:0008366), positive regulation of gene expression (GO:0010628), astrocyte development (GO:0014002), substantia nigra development (GO:0021762), central nervous system myelination (GO:0022010), long-chain fatty acid biosynthetic process (GO:0042759), axon development (GO:0061564), myelination (GO:0042552)

GO Molecular Function (4): structural molecule activity (GO:0005198), structural constituent of myelin sheath (GO:0019911), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), myelin sheath (GO:0043209), synapse (GO:0045202), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
defense response	1
anterograde trans-synaptic signaling	1
ensheathment of neurons	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
glial cell development	1
astrocyte differentiation	1
midbrain development	1
neural nucleus development	1
oligodendrocyte development	1
axon ensheathment in central nervous system	1
myelination	1
long-chain fatty acid metabolic process	1
fatty acid biosynthetic process	1
neuron projection development	1
axon ensheathment	1
molecular_function	1
structural molecule activity	1
myelin sheath	1
protein binding	1
binding	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

30 interactions, top by confidence:

A	B	Type	Score
PTPRN	PLP1	psi-mi:“MI:0915”(physical association)	0.560
PLP1	PTPRN	psi-mi:“MI:0915”(physical association)	0.560
PLP1	BCL2L13	psi-mi:“MI:0915”(physical association)	0.560
PLP1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	NCF2	psi-mi:“MI:0914”(association)	0.530
APP	PLP1	psi-mi:“MI:0915”(physical association)	0.510
PLP1	HTR2C	psi-mi:“MI:0915”(physical association)	0.370
TRPV2	PLP1	psi-mi:“MI:0915”(physical association)	0.370
PTPRN	PLP1	psi-mi:“MI:0915”(physical association)	0.370
PLP1	AKT1	psi-mi:“MI:0915”(physical association)	0.370
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
PRNP	SYNJ1	psi-mi:“MI:0914”(association)	0.350
PRNP	MBP	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
U2AF1	RGPD2	psi-mi:“MI:0914”(association)	0.350
PLP1	REEP5	psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	PLP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (127): PTPRN (Two-hybrid), ITGB5 (Affinity Capture-Western), ITGAV (Affinity Capture-Western), CALR (Affinity Capture-Western), PLP1 (Two-hybrid), PTPRN (Two-hybrid), CREB3 (Two-hybrid), CREB3L1 (Two-hybrid), PTPRN (Two-hybrid), REEP6 (Affinity Capture-MS), FGFR1OP2 (Affinity Capture-MS), SLMAP (Affinity Capture-MS), REEP5 (Affinity Capture-MS), STRN (Affinity Capture-MS), SIKE1 (Affinity Capture-MS)

ESM2 similar proteins: A2VDC7, A4FUZ5, A9CAZ8, B9TRX0, O15243, O89013, O95807, P04116, P23289, P23294, P36963, P36965, P47789, P47790, P56557, P60201, P60202, P60203, Q0P442, Q0P467, Q13491, Q13530, Q1E1E0, Q3SYT0, Q3SZL9, Q3T110, Q3ZC23, Q4R6L9, Q561T9, Q566G2, Q5PSV5, Q5R4C3, Q5R533, Q5R603, Q5R6E6, Q5ZJD9, Q712P7, Q7TNK0, Q7Z0Q2, Q803X0

Diamond homologs: P04116, P23289, P23290, P23294, P35801, P35802, P35803, P36963, P36964, P36965, P47789, P47790, P51674, P60201, P60202, P60203, P79826, Q0VD07, Q13491, Q5R603, Q5R6E6, Q5R9Q3, Q712P7, Q812E9, Q8HXW7, Q9JJK1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLP1	up-regulates	Myelination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
central nervous system development	5	27.5×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

406 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	90
Uncertain significance	117
Likely benign	57
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028820	NM_000533.5(PLP1):c.21T>A (p.Cys7Ter)	Pathogenic
1068867	NC_000023.10:g.(?103031924)(103045526_?)dup	Pathogenic
11076	NM_000533.5(PLP1):c.467C>T (p.Thr156Ile)	Pathogenic
11079	NM_000533.5(PLP1):c.544A>C (p.Thr182Pro)	Pathogenic
11082	NM_000533.5(PLP1):c.220G>A (p.Gly74Arg)	Pathogenic
11083	NM_000533.5(PLP1):c.661G>T (p.Gly221Cys)	Pathogenic
11091	NM_000533.5(PLP1):c.725C>T (p.Ala242Val)	Pathogenic
11099	NM_000533.5(PLP1):c.169G>T (p.Asp57Tyr)	Pathogenic
1335786	NM_000533.5(PLP1):c.684C>A (p.Cys228Ter)	Pathogenic
1458915	NC_000023.10:g.(?103031003)(103031929_?)del	Pathogenic
1459546	NM_000533.5(PLP1):c.205C>T (p.Gln69Ter)	Pathogenic
1695310	NM_000533.5(PLP1):c.354del (p.Gly120fs)	Pathogenic
1698358	NM_000533.5(PLP1):c.454-10A>G	Pathogenic
1809199	GRCh37/hg19 Xq22.2(chrX:103017429-103236332)x3	Pathogenic
1932099	NM_000533.5(PLP1):c.142_152del (p.Glu48fs)	Pathogenic
2015521	NM_000533.5(PLP1):c.553C>T (p.Gln185Ter)	Pathogenic
2043641	NM_000533.5(PLP1):c.435G>A (p.Trp145Ter)	Pathogenic
209183	NM_000533.5(PLP1):c.1A>G (p.Met1Val)	Pathogenic
2138679	NM_000533.5(PLP1):c.697-1G>A	Pathogenic
2423244	NC_000023.10:g.(?103031924)(103045526_?)del	Pathogenic
2423246	NC_000023.10:g.(?103042707)(103045526_?)del	Pathogenic
2423248	NC_000023.10:g.(?103040922)(103042832_?)del	Pathogenic
253460	GRCh37/hg19 Xq22.2(chrX:103031174-103046823)x0	Pathogenic
2581156	NM_000533.5(PLP1):c.454-1G>A	Pathogenic
265341	NM_000533.5(PLP1):c.762+2T>C	Pathogenic
265417	NM_000533.5(PLP1):c.607G>A (p.Asp203Asn)	Pathogenic
267338	NC_000023.10:g.(?103031918)(103045531_?)dup	Pathogenic
2704479	NM_000533.5(PLP1):c.176_177dup (p.Tyr60fs)	Pathogenic
280862	NM_000533.5(PLP1):c.191+1G>T	Pathogenic
2815078	NM_000533.5(PLP1):c.406G>T (p.Glu136Ter)	Pathogenic

SpliceAI

1094 predictions. Top by Δscore:

Variant	Effect	Δscore
X:103776735:G:GT	donor_gain	1.0000
X:103777000:G:GG	donor_gain	1.0000
X:103785577:CCCA:C	acceptor_loss	1.0000
X:103785578:CCA:C	acceptor_loss	1.0000
X:103785579:CA:C	acceptor_loss	1.0000
X:103785580:A:AG	acceptor_gain	1.0000
X:103785581:G:A	acceptor_loss	1.0000
X:103785581:G:GA	acceptor_gain	1.0000
X:103785581:GGCTT:G	acceptor_gain	1.0000
X:103785765:ATGT:A	donor_gain	1.0000
X:103785765:ATGTG:A	donor_loss	1.0000
X:103785767:GT:G	donor_gain	1.0000
X:103785768:TGTA:T	donor_loss	1.0000
X:103785769:G:GG	donor_gain	1.0000
X:103785770:TAAG:T	donor_loss	1.0000
X:103786518:AT:A	acceptor_gain	1.0000
X:103786518:ATG:A	acceptor_gain	1.0000
X:103786518:ATGG:A	acceptor_gain	1.0000
X:103786518:ATGGG:A	acceptor_gain	1.0000
X:103786519:T:G	acceptor_gain	1.0000
X:103786519:T:TA	acceptor_gain	1.0000
X:103786520:G:A	acceptor_gain	1.0000
X:103786603:C:T	donor_gain	1.0000
X:103786607:GGCC:G	donor_gain	1.0000
X:103786608:GCC:G	donor_gain	1.0000
X:103788433:TTAGG:T	acceptor_loss	1.0000
X:103788434:TAGGT:T	acceptor_loss	1.0000
X:103788435:AGGTG:A	acceptor_loss	1.0000
X:103788436:G:GA	acceptor_loss	1.0000
X:103788436:GGT:G	acceptor_gain	1.0000

AlphaMissense

1794 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:103787831:T:A	W163R	1.000
X:103787831:T:C	W163R	1.000
X:103787895:G:A	C184Y	1.000
X:103788497:G:A	C228Y	1.000
X:103789372:G:A	G246R	1.000
X:103789372:G:C	G246R	1.000
X:103785659:G:A	G28R	0.999
X:103785659:G:C	G28R	0.999
X:103785674:T:C	C33R	0.999
X:103785696:T:A	L40H	0.999
X:103785696:T:C	L40P	0.999
X:103785714:T:C	L46P	0.999
X:103787862:C:A	P173H	0.999
X:103787862:C:G	P173R	0.999
X:103787894:T:A	C184S	0.999
X:103787894:T:C	C184R	0.999
X:103787895:G:C	C184S	0.999
X:103787896:C:G	C184W	0.999
X:103787945:T:A	C201S	0.999
X:103787945:T:C	C201R	0.999
X:103787946:G:A	C201Y	0.999
X:103787946:G:C	C201S	0.999
X:103787947:T:G	C201W	0.999
X:103788472:T:C	C220R	0.999
X:103788473:G:A	C220Y	0.999
X:103788474:T:G	C220W	0.999
X:103788496:T:A	C228S	0.999
X:103788496:T:C	C228R	0.999
X:103788497:G:C	C228S	0.999
X:103788498:C:G	C228W	0.999

dbSNP variants (sampled 300 via entrez): RS1000071136 (X:103776956 C>A,G), RS1000561231 (X:103777790 G>A), RS1000629759 (X:103780053 T>G), RS1001002923 (X:103774993 G>A,T), RS1001639060 (X:103778928 C>A,T), RS1001843437 (X:103775679 A>G), RS1001877652 (X:103776545 C>G), RS1001971446 (X:103787184 G>A,T), RS1002372548 (X:103776903 A>G), RS1002504411 (X:103780651 G>A), RS1002700430 (X:103782903 C>T), RS1002815311 (X:103783383 C>T), RS1002988441 (X:103780089 C>T), RS1003640479 (X:103774866 A>G), RS1003737528 (X:103790291 T>C)

Disease associations

OMIM: gene MIM:300401 | disease phenotypes: MIM:312920, MIM:312080, MIM:303350, MIM:173900

GenCC curated gene-disease

Disease	Classification	Inheritance
Pelizaeus-Merzbacher spectrum disorder	Definitive	X-linked
hereditary spastic paraplegia 2	Definitive	X-linked
Pelizaeus-Merzbacher disease, connatal form	Supportive	X-linked
Pelizaeus-Merzbacher disease, classic form	Supportive	X-linked
Pelizaeus-Merzbacher disease, transitional form	Supportive	X-linked
Pelizaeus-Merzbacher disease in female carriers	Supportive	X-linked
null syndrome	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Pelizaeus-Merzbacher spectrum disorder	Definitive	XL

Mondo (10): hereditary spastic paraplegia 2 (MONDO:0010733), Pelizaeus-Merzbacher spectrum disorder (MONDO:0010714), hereditary spastic paraplegia (MONDO:0019064), polycystic kidney disease 1 (MONDO:0008263), intellectual disability (MONDO:0001071), Pelizaeus-Merzbacher disease, connatal form (MONDO:0017221), Pelizaeus-Merzbacher disease, classic form (MONDO:0017222), Pelizaeus-Merzbacher disease, transitional form (MONDO:0017223), Pelizaeus-Merzbacher disease in female carriers (MONDO:0017224), null syndrome (MONDO:0017225)

Orphanet (4): Spastic paraplegia type 2 (Orphanet:99015), Pelizaeus-Merzbacher disease (Orphanet:702), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

128 total (30 of 128 shown, HPO-id order):

HPO	Term
HP:0000011	Neurogenic bladder
HP:0000012	Urinary urgency
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000490	Deeply set eye
HP:0000511	Vertical supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000716	Depression
HP:0000741	Apathy
HP:0000750	Delayed speech and language development
HP:0000762	Decreased nerve conduction velocity
HP:0000763	Sensory neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001266	Choreoathetosis
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020371	Pelizaeus-Merzbacher Disease	C10.228.140.163.100.362.775; C10.228.140.695.625.775; C10.314.400.775; C16.320.322.906; C16.320.565.189.362.775; C18.452.132.100.362.775; C18.452.648.189.362.775
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C536326	Polycystic kidney disease, type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, affects cotreatment	4
Valproic Acid	decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	3
Cocaine	affects expression, decreases expression	3
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
fluorene-9-bisphenol	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
quinocetone	increases expression	1
dorsomorphin	decreases expression, increases expression, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Ethanol	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases expression	1
Cytarabine	increases expression	1
Etoposide	affects response to substance	1
Ivermectin	decreases expression	1
Malathion	decreases expression	1
Nickel	decreases expression	1
Oxygen	decreases expression	1
Quercetin	decreases expression	1
Tretinoin	decreases expression	1
Vanadates	increases expression	1
Oxyquinoline	decreases expression	1

Cellosaurus cell lines

18 cell lines: 9 induced pluripotent stem cell, 8 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5P74	GM13433	Transformed cell line	Male
CVCL_5P75	GM13434	Transformed cell line	Male
CVCL_5P76	GM13435	Transformed cell line	Male
CVCL_5P77	GM13436	Transformed cell line	Male
CVCL_5P78	GM13437	Transformed cell line	Male
CVCL_7493	GM09545	Transformed cell line	Male
CVCL_D6MC	RUCDRi002-A-69	Induced pluripotent stem cell	Male
CVCL_F209	GM09546	Finite cell line	Male
CVCL_F211	GM09548	Transformed cell line	Female
CVCL_W206	GM07157	Transformed cell line	Male

Clinical trials (associated diseases)

257 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT07382739	PHASE2	RECRUITING	A Phase 2 Study of Radiotherapy-induced Immune Priming to Enhance Elranatamab (Elra) in Relapsed Refractory Multiple Myeloma (RRMM) With Extramedullary Disease (EMD) and Paramedullary Disease (PMD) PRIME-EMD-PMD
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01005004	PHASE1	COMPLETED	Study of Human Central Nervous System (CNS) Stem Cells Transplantation in Pelizaeus-Merzbacher Disease (PMD) Subjects
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT06150716	PHASE1	RECRUITING	Orbit Study: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Participants With Pelizaeus Merzbacher Disease (PMD)
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01391637	Not specified	COMPLETED	Long-Term Follow-Up Study of Human Stem Cells Transplanted in Subjects With Connatal Pelizaeus-Merzbacher Disease (PMD)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT05659901	Not specified	RECRUITING	Rocket Study: A Study to Characterize Biomarkers and Disease Progression in Participants With Pelizaeus-Merzbacher Disease
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4