MAG

protein-coding

myelin associated glycoprotein, the group of I-set domain containing|C2-set domain containing|Sialic acid binding Ig like lectins

Gene summary

The protein encoded by this gene is a type I membrane protein and member of the immunoglobulin superfamily. It is thought to be involved in the process of myelination. It is a lectin that binds to sialylated glycoconjugates and mediates certain myelin-neuron cell-cell interactions. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2010]

Previous symbols:

MANE transcript

NM_002361.4

Inheritance

ClinVar variants

P:15U:173B:129

Top phenotype

Spastic paraplegia, autosomal recessive 75

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr19:35,292,125-35,313,807

External References & Databases

Ensembl (ENSG00000105695)

Transcript & Mutation Effects

hg38 • Region Span ~21.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex hereditary spastic paraplegiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: PanelApp Australia

complex hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*MAG* encodes a transmembrane, cell adhesion molecule in the periaxonal layer of mature, non-compact myelin membranes, and maintains myelin-axon spacing by interacting with specific neuronal glycolipids (gangliosides) (PMIDs: 26179919; 27922006). *MAG* was first reported in relation to ‘complex’ autosomal recessive hereditary spastic paraplegia (HSP) in 2014 (PMID: 26179919). Hereditary spastic paraplegia refers to a group of inherited disorders that are characterised by progressive weakness and spasticity of the lower limbs. The term ‘complex’ is included as all individuals presented with additional neurological phenotypes such as ataxia, eye phenotypes, cognitive impairments, and vibratory sense deficits. Age of onset was typically in infancy and early childhood. Symptoms were slowly progressive and can sometimes present early as a static clinical course. Ten variants (missense and nonsense) have been reported in 8 families in 5 publications. We have included 6 probands and 7 variants in this curation (PMIDs: 26179919, 32629324, 27606346). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) had been reached (additional PMID: 24482476, 31402626). There was no functional evidence for any of the nonsense variants; however, functional evidence for two missense variants were included in the curation. The p.Ser133Arg variants showed accumulation of terminally misfolded proteins in the endoplasmic reticulum leading to their degradation (PMID: 26179919), and p.Arg118Ala/Asp variants demonstrated loss of activity of a highly conserved sialic acid binding site (PMID: 9298990). These studies support the assumption that variants in *MAG* are responsible for the patients’ phenotypes by acting through a loss of protein function activity. This gene-disease relationship is further supported by a *MAG* knockout murine model (PMID: 34546337). The gene was disrupted by insertion of PGK-neo cassette into exon 5. Absence of gene expression was confirmed by Western blot analysis of brains from 26-day-old homozygous mutant mice. Mice showed abnormal Schwann cell morphology, abnormal axon morphology, axon degeneration, and demyelination. In summary, there is a definitive relationship between *MAG* and autosomal recessive complex HSP. 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 Cerebral Palsy Gene Curation Expert Panel on 20th November, 2023 (SOP Version 9).

hereditary spastic paraplegia 75STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014729

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 75SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014729

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic paraplegia, autosomal recessive 75AR

Manifestation: Neurologic

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: 24482476; 26179919

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAG variants in ClinVar

7 Conditions Cataloged

Hereditary spastic paraplegia 75Total: 268

Inborn genetic diseasesTotal: 110

not providedTotal: 44

not specifiedTotal: 21

MAG-related disorderTotal: 16

Hereditary spastic paraplegiaTotal: 3

Orofacial cleft 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002361.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	113 clinvar	3 clinvar	117
missense	3 clinvar	2 clinvar	171 clinvar	10 clinvar	3 clinvar	189
nonsense	3 clinvar	1 clinvar				4
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)		3 clinvar				3
Total	8	7	173	123	6	317

Highest pathogenic variant AF is 0.0000050890512

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002361.4	RefSeq	NP_002352.1	9	MANE Select
ENST00000392213.8	Ensembl	ENSP00000376048.2	9	MANE Select
NM_001199216.2	RefSeq	NP_001186145.1	8	Standard
NM_080600.3	RefSeq	NP_542167.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Glial Cell Differentiation
Spinal Cord Injury
MECP2 and Associated Rett Syndrome
Signal Transduction

Biological Process

cell adhesion
negative regulation of neuron projection development
transmission of nerve impulse
central nervous system myelination
negative regulation of axon extension

Molecular Function

signaling receptor binding
protein kinase binding
carbohydrate binding
sialic acid binding
protein homodimerization activity

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
paranode region of axon
myelin sheath adaxonal region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392213
Coding exons: 9
Length: 21680
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	348	413	0.843	0.0000283	3996
Missense (PolyPhen)		71	113.28	0.62675		1114
Synonymous	0.184	192	195	0.983	0.0000150	1333
Loss of Function	3.84	6	27.9	0.215	0.00000159	277

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adhesion molecule that mediates interactions between myelinating cells and neurons by binding to neuronal sialic acid- containing gangliosides and to the glycoproteins RTN4R and RTN4RL2 (By similarity). Not required for initial myelination, but seems to play a role in the maintenance of normal axon myelination. Protects motoneurons against apoptosis, also after injury; protection against apoptosis is probably mediated via interaction with neuronal RTN4R and RTN4RL2. Required to prevent degeneration of myelinated axons in adults; this probably depends on binding to gangliosides on the axon cell membrane (By similarity). Negative regulator of neurite outgrowth; in dorsal root ganglion neurons the inhibition is mediated primarily via binding to neuronal RTN4R or RTN4RL2 and to a lesser degree via binding to neuronal gangliosides. In cerebellar granule cells the inhibition is mediated primarily via binding to neuronal gangliosides. In sensory neurons, inhibition of neurite extension depends only partially on RTN4R, RTN4RL2 and gangliosides. Inhibits axon longitudinal growth (By similarity). Inhibits axon outgrowth by binding to RTN4R (By similarity). Preferentially binds to alpha- 2,3-linked sialic acid. Binds ganglioside Gt1b (By similarity). {ECO:0000250|UniProtKB:P07722, ECO:0000250|UniProtKB:P20917}.;
Disease: DISEASE: Spastic paraplegia 75, autosomal recessive (SPG75) [MIM:616680]: 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. SPG75 is characterized by onset in early childhood and is associated with mild to moderate cognitive impairment. {ECO:0000269|PubMed:24482476, ECO:0000269|PubMed:26179919, ECO:0000269|PubMed:27606346}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.267

Intolerance Scores

LoFtool: 0.476
RVIS EVS: -0.2
RVIS percentile EVS: 39.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.871

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium