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Relevance to Autism

Truncating variants on the paternal allele of the MAGEL2 gene were identified in four individuals presenting with autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of Prader-Willi syndrome (PWS) (Schaaf et al., 2013).

Molecular Function

The protein encoded by this paternally-imprinted gene may enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases and has been proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. This gene may play a role in Prader-Willi syndrome (PWS, OMIM 176270), a contiguous gene syndrome characterized by muscular hypotonia, mental retardation, short stature, obesity, hypogonadotropic hypogonadism, and small hands and feet that results from inactivity of the paternal copies of a number of genes on 15q11, through deletion or disruption of these genes or maternal uniparental disomy 15.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.
Schaaf-Yang syndrome
ASD, ID
Support
The adult phenotype of Schaaf-Yang syndrome
Schaaf-Yang syndrome
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID
Support
MAGEL2-related disorders: A study and case series.
Schaaf-Yang syndrome
ASD, ADHD
Support
A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes.
Schaaf-Yang syndrome
Features of Opitz trigonocephaly C syndrome, ID
Support
Neurocognitive and Neurobehavioral Phenotype of Youth with Schaaf-Yang Syndrome.
Schaaf-Yang syndrome
ASD
Support
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Schaaf-Yang syndrome
DD, microcephaly
Support
A Novel Mutation of MAGEL2 in a Patient with Schaaf-Yang Syndrome and Hypopituitarism.
Schaaf-Yang syndrome
ASD
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Support
Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders.
Chitayat-Hall syndrome
ASD
Support
Phenotypic spectrum and mechanism analysis of Schaff Yang syndrome: A case report on new mutation of MAGEL2 gene
Schaaf-Yang syndrome
DD, ID, autistic features
Support
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.
Schaaf-Yang syndrome
DD, ASD
Support
Three patients with Schaaf-Yang syndrome exhibiting arthrogryposis and endocrinological abnormalities.
Schaaf-Yang syndrome
Autistic behavior
Support
Diagnosis of Schaaf-Yang syndrome in Korean children with developmental delay and hypotonia
Schaaf-Yang syndrome, DD
ASD or autistic features, epilepsy/seizures
Support
Pitfalls of trio-based exome sequencing: imprinted genes and parental mosaicism-MAGEL2 as an example.
Schaaf-Yang syndrome
DD
Recent Recommendation
Schaaf-Yang syndrome overview: Report of 78 individuals.
Schaaf-Yang syndrome
ASD
Recent Recommendation
Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.
Recent Recommendation
The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.
Schaaf-Yang syndrome
DD, ID, ASD, epilepsy/seizures
Recent Recommendation
Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.
AMC

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN578R001 
 frameshift_variant 
 c.1652del 
 p.Val551AspfsTer151 
 De novo 
 NA 
 Simplex 
 GEN578R002 
 frameshift_variant 
 c.1802del 
 p.Pro601GlnfsTer101 
 Unknown 
 Not maternal 
  
 GEN578R003 
 frameshift_variant 
 c.3181_3182del 
 p.Ile1061HisfsTer7 
 De novo 
 NA 
  
 GEN578R004 
 stop_gained 
 c.3124C>T 
 p.Gln1042Ter 
 De novo 
 NA 
  
 GEN578R005 
 frameshift_variant 
 c.1996del 
 p.Gln666SerfsTer36 
 Familial 
 Paternal 
 Multiplex 
 GEN578R006 
 frameshift_variant 
 c.2118del 
 p.Leu708TrpfsTer7 
 De novo 
 NA 
 Simplex 
 GEN578R007 
 frameshift_variant 
 c.1996dupC 
 p.Gln666ProfsTer47 
 De novo 
 NA 
 Multiplex 
 GEN578R008 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 Familial 
 Paternal 
 Extended multiplex 
 GEN578R009 
 stop_gained 
 c.3235G>T 
 p.Glu1079Ter 
 Familial 
 Paternal 
  
 GEN578R010 
 stop_gained 
 c.1912C>T 
 p.Gln638Ter 
 De novo 
 NA 
  
 GEN578R011 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 Familial 
 Paternal 
 Multiplex 
 GEN578R012 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 De novo 
 NA 
  
 GEN578R013 
 stop_gained 
 c.1621C>T 
 p.Gln541Ter 
 Familial 
 Paternal 
  
 GEN578R014 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 De novo 
 NA 
  
 GEN578R015 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 De novo 
 NA 
  
 GEN578R016 
 stop_gained 
 c.2873G>A 
 p.Trp958Ter 
 Unknown 
  
  
 GEN578R017 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 De novo 
 NA 
  
 GEN578R018 
 frameshift_variant 
 c.1580del 
 p.Pro527ArgfsTer175 
 Unknown 
  
  
 GEN578R019 
 frameshift_variant 
 c.1801_1802del 
 p.Pro601AsnfsTer111 
 Unknown 
  
  
 GEN578R020 
 frameshift_variant 
 c.1996dupC 
 p.Gln666fs 
 De novo 
 NA 
  
 GEN578R021 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 Familial 
 Paternal 
 Extended multiplex 
 GEN578R022 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 De novo 
 NA 
  
 GEN578R023 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 De novo 
 NA 
 Simplex 
 GEN578R024 
 stop_gained 
 c.1912C>T 
 p.Gln638Ter 
 De novo 
 NA 
 Simplex 
 GEN578R025 
 stop_gained 
 c.3208G>T 
 p.Glu1070Ter 
 De novo 
 NA 
  
 GEN578R026 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 Familial 
 Paternal 
 Simplex 
 GEN578R027 
 stop_gained 
 c.1912C>T 
 p.Gln638Ter 
 Familial 
 Paternal 
 Multiplex 
 GEN578R028 
 stop_gained 
 c.3131C>A 
 p.Ser1044Ter 
 De novo 
 NA 
 Simplex 
 GEN578R029a 
 complex_structural_alteration 
  
  
 Familial 
 Paternal 
 Multi-generational 
 GEN578R029b 
 complex_structural_alteration 
  
  
 Familial 
 Paternal 
 Multi-generational 
 GEN578R029c 
 complex_structural_alteration 
  
  
 Familial 
 Paternal 
 Multi-generational 
 GEN578R030 
 stop_gained 
 c.1762C>T 
 p.Gln588Ter 
 Unknown 
  
 Multiplex 
 GEN578R031 
 frameshift_variant 
 c.2179_2180del 
 p.Asp727ProfsTer6 
  
  
 Multiplex 
 GEN578R032 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 Familial 
 Paternal 
 Simplex 
 GEN578R033 
 stop_gained 
 c.3019C>T 
 p.Gln1007Ter 
 De novo 
 NA 
  
 GEN578R034 
 frameshift_variant 
 c.3122del 
 p.Val1041AlafsTer7 
 De novo 
 NA 
 Simplex 
 GEN578R035 
 missense_variant 
 c.1613C>A 
 p.Ala538Glu 
 Familial 
 Paternal 
 Simplex 
 GEN578R036 
 frameshift_variant 
 c.1996_1997insCA 
 p.Gln666ProfsTer37 
 Familial 
 Paternal 
 Simplex 
 GEN578R037 
 stop_gained 
 c.3169G>T 
 p.Glu1057Ter 
 De novo 
 NA 
 Simplex 
 GEN578R038 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 De novo 
 NA 
  
 GEN578R039 
 stop_gained 
 c.2874G>A 
 p.Trp958Ter 
 De novo 
 NA 
  
 GEN578R040 
 frameshift_variant 
 c.1800del 
 p.Pro601GlnfsTer101 
 De novo 
 NA 
  
 GEN578R041 
 stop_gained 
 c.1819C>T 
 p.Gln607Ter 
 Familial 
 Paternal 
  
 GEN578R042 
 frameshift_variant 
 c.2958del 
 p.Ser987AlafsTer5 
 De novo 
 NA 
  
 GEN578R043 
 frameshift_variant 
 c.1790del 
 p.Pro597HisfsTer105 
 Unknown 
  
  
 GEN578R044 
 frameshift_variant 
 c.2821dup 
 p.Arg941ProfsTer10 
 Unknown 
  
  
 GEN578R045 
 inframe_insertion 
 c.2170_2171insTCTTCTATAGACCGCAGGGGCTCCTCTAAAGAGCGCAGGACCTCCTCGAAGGAGCGCAGGGCC 
 p.Ser724delinsPhePheTyrArgProGlnGlyLeuLeuTer 
 Unknown 
  
  
 GEN578R046 
 frameshift_variant 
 c.1996dupC 
 p.Gln666ProfsTer47 
 Familial 
 Paternal 
  
 GEN578R047 
 frameshift_variant 
 c.1996dup 
 p.Gln666ProfsTer47 
 De novo 
 NA 
  
 GEN578R048 
 frameshift_variant 
 c.2217del 
 p.Lys740ArgfsTer11 
 De novo 
 NA 
 Simplex 
 GEN578R049 
 frameshift_variant 
 c.3449_3450del 
 p.Phe1150TrpfsTer4 
 Familial 
 Paternal 
 Simplex 
 GEN578R050 
 stop_gained 
 c.1687C>T 
 p.Gln563Ter 
 Unknown 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
15
Duplication
 10
  construct
15
Duplication
 1
 
15
Duplication
 3
 
15
Duplication
 7
 
15
Duplication
 2
 
15
Duplication
 2
 
15
Deletion
 1
 
15
Deletion-Duplication
 98
 
15
Duplication
 7
 
15
Duplication
 66
  construct
15
Duplication
 5
 
15
Duplication
 14
 
15
Duplication
 3
 
15
Duplication
 1
 

Model Summary

Magel2 KO mice display increased weight gain post weaning and circadian rhythm abnormalities.

References

Type
Title
Author, Year
Additional
Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome.
Primary
The imprinted gene Magel2 regulates normal circadian output.
Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes.

M_MAGEL2_1_KO_HT_M+P-

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: The entire open reading frame was replaced with a lacZ-neo cassette. The endogenous promoter drives the expression of lacZ as confirmed by a beta-galactosidase assay. The absence of the paternal transcript was confirmed by RT-PCR. Effectively, Magel2 m+p- mice are nulls as the maternal transcript is not expressed.
Allele Type: Targeted (Reporter)
Strain of Origin: B6.Cg-Thy1a
Genetic Background: C57BL/6-Magel2tm1Stw
ES Cell Line:
Mutant ES Cell Line:
Model Source: JAX

M_MAGEL2_1_KO_HT_M+P-

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle2
Decreased
Description: Magel2 nulls have decreased vertical activity in both light and dark cycles
Exp Paradigm: Male; general observations
 General observations
 10-12 weeks
Circadian rhythm1
Abnormal
Description: Magel2m+p- mice ran significantly less with a shorter average bout length than the wild type controls during the period of constant darkness. the percentage of daily activity was also significantly lower in magel2 m+p- mice as well
Exp Paradigm: NA
 Running wheel test
 8 months
Motor strength and endurance2
Decreased
Description: Decreased endurance in magel2 female nulls
Exp Paradigm: Female; progressive treadmill test
 Progressive treadmill test
 14 and 22 weeks
Grip strength2
Decreased
Description: Hindlimb grip strength declined more rapidly with age in magel2 null mice when compared to wildtype controls
Exp Paradigm: Grip strength test
 Grip strength test
 2-40 weeks
Brain cytoarchitecture1
Decreased
Description: A decrease in the number of orexin positive neurons was seen in the hypothalamus of magel2m+p- mice. the amount of orexin2 receptors was also substantially reduced in the hypothalamus
Exp Paradigm: Immunostaining
 Immunostaining
 Unreported
Macroautophagy: neuronal2
Decreased
Description: Decreased detection of ubiquitin or p62 (sqstm1, sequestosome 1), an macroautophagy marker, in magel2 null pomc-positive neurons
Exp Paradigm: Immunostaining: ubiquitin, sqstm1
 Immunostaining
 NA
Tissue weight2
Decreased
Description: Limb muscle weight (gastrocnemius-soleus-plantaris, quadriceps, and tibialis anterior) is reduced with normal muscle histology in the magel2 null mice
Exp Paradigm: Measurement of tissue weight; histology
 Measurement of tissue weight
 10-28 weeks
Mortality/lethality3
Increased
Description: Magel2m+p- pups were reduced in number than expected, reduced viability was seen at e12.5
Exp Paradigm: NA
 General observations
 Unreported
Size/growth3
Abnormal
Description: There was no difference in the birth weight of magel2 m+p- pups, however growth retardation was observed from p7 until weaning between p21 and p28. by 5-6 weeks of age, the weight normalized to wild type levels. between 5-12 weeks of age magel2 m+p- mice showed some increased weight gain
Exp Paradigm: NA
 General observations
 Unreported
Mortality/lethality1
Increased
Description: Magel2 m+p- mice were weaned at approximately 10% lower frequency suggesting lower early postnatal viability
Exp Paradigm: NA
 General observations
 3 weeks
Reproductive system development1
Decreased
Description: The mating frequency of males declined by 16 weeks of age and eventually ceased
Exp Paradigm: NA
 General observations
 8-16 weeks
Developmental trajectory1
Decreased
Description: Magel2m+p- mice showed significantly lower food intake
Exp Paradigm: After starvation for 24 hr, food intake was monitored for 48 hr, provided ad libitum
 Feeding habit observation after starvation
 6 weeks
Vertebrae morphology2
Decreased
Description: Mild spinal curvatures with upward rotation of the right aspect of the skull and a righward thoracic curve in magel2 null mice
Exp Paradigm: Skeletal x-rays
 Skeletal x-rays
 NA
Muscular fiber morphology2
Decreased
Description: The percentage of larger fibres is higher in the soleus muscle and lower in the gastrocnemius muscle of magel2 nulls when compared to the wildtype controls
Exp Paradigm: Histology; immunostaining: dystrophin
 Immunohistochemistry
 NA
Macroautophagy2
Increased
Description: Increased expression of p62 (sqstm1, sequestosome 1), an macroautophagy marker, in magel2 null muscles
Exp Paradigm: Immunostaining: sqstm1
 Immunostaining
 Adult
Gene expression2
Increased
Description: Increased expression of murf1 (trim63), an atrophy gene, in magel2 null muscles
Exp Paradigm: Quantitative pcr (qrt-pcr): murf1
 Quantitative pcr (qrt-pcr)
 P2 and adult
Muscular fiber morphology2
 No change
 Immunostaining
 NA
Reproductive system development1
 No change
 General observations
 Adult
Size/growth2
 No change
 Skeletal x-rays
 NA
Size/growth1
 No change
 General observations
 0-24 months
Skeletal development: appendages (limbs, digits, tail)2
 No change
 Skeletal x-rays
 NA
Skeletal development: craniofacial2
 No change
 Skeletal x-rays
 NA
Cell differentiation2
 No change
 Quantitative pcr (qrt-pcr)
 NA
Gene expression2
 No change
 Western blot
 NA
Regulation of gene expression1
 No change
 Western blot
 Unreported
Motor strength and endurance2
 No change
 Progressive treadmill test
 14 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
SNRPN small nuclear ribonucleoprotein polypeptide N 6638 P63162 in vitro methylation assay; Chromatin conformation capture
Rabinovitz S , et al. 2012
TRIM27 tripartite motif-containing 27 5987 P14373 TAP; MS; IP/WB
Hao YH , et al. 2013
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010
USP7 ubiquitin specific peptidase 7 (herpes virus-associated) 7874 Q93009 TAP; MS; IP/WB
Hao YH , et al. 2013
USP7 ubiquitin specific peptidase 7 (herpes virus-associated) 7874 Q93009 in vitro binding assay; IP/WB
Hao YH , et al. 2015
VPS26A vacuolar protein sorting 26 homolog A (S. pombe) 9559 O75436 TAP; MS; IP/WB
Hao YH , et al. 2013
VPS35 vacuolar protein sorting 35 homolog (S. cerevisiae) 55737 Q96QK1 TAP; MS; IP/WB
Hao YH , et al. 2013

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