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Relevance to Autism

Several studies have identified rare mutations in the SHANK2 gene in autistic and intellectually disabled individuals (Berkel et al., 2010; Pinto et al., 2010; Leblond et al., 2012; Sanders et al., 2012). A functional study analyzed three of the mutations previously found in individuals with ASD (L1008_P1009dup, T1127M and R462X). The mutations were found to have varying effects on protein localization, dendritic spine volume and branching in cultured neurons and even synaptic transmission and cognitive behavior in mice, with the R462X variant causing the most severe phenotypes (Berkel et al., 2012).

Molecular Function

Shank proteins contain multiple domains for protein-protein interactions and function as molecular scaffolds in the postsynaptic density (PSD).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.
ASD
MR
Positive Association
Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder.
ASD
Negative Association
Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.
ASD
Support
Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...
DD, ID
Autistic behavior
Support
A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders.
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID, ADHD
Support
Characterization of intellectual disability and autism comorbidity through gene panel sequencing.
ID, ASD or autistic traits
Support
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.
ID
Epilepsy, ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.
ASD
Support
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
ASD
Support
Genome-wide characteristics of de novo mutations in autism
ASD
Support
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...
ASD
Support
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
ASD
ID
Support
Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.
SCZ
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Functional impact of global rare copy number variation in autism spectrum disorders.
ASD
Support
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.
DD, ID
Support
Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluo...
ASD, OCD
Highly Cited
Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.
Highly Cited
The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.
Highly Cited
The Shank family of scaffold proteins.
Recent Recommendation
Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.
ASD
ID
Recent Recommendation
SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons.
ASD
Recent Recommendation
Activity induced changes in the distribution of Shanks at hippocampal synapses.
Recent Recommendation
Effect of the autism-associated lncRNA Shank2-AS on architecture and growth of neurons.
Recent Recommendation
BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
AnkyrinG is required to maintain axo-dendritic polarity in vivo.
Recent Recommendation
Identification and functional characterization of rare SHANK2 variants in schizophrenia.
SCZ
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Recent Recommendation
Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.
ASD
Recent Recommendation
Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN229R001 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN229R002 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN229R003 
 stop_gained 
 c.1235G>A 
 p.Arg412His 
 De novo 
 NA 
 Simplex 
 GEN229R004 
 missense_variant 
 c.76G>A 
 p.Asp26Asn 
 Familial 
 Paternal 
  
 GEN229R005 
 missense_variant 
 c.622G>A 
 p.Asp208Asn 
 Familial 
 Maternal 
 Multiplex 
 GEN229R006 
 missense_variant 
 c.622G>A 
 p.Asp208Asn 
 Unknown 
  
 Simplex 
 GEN229R007 
 missense_variant 
 c.692C>A 
 p.Ser231Tyr 
 Familial 
 Paternal 
 Simplex 
 GEN229R008 
 inframe_insertion 
 c.4642_4643insTCTCCA 
 p.Ser1548delinsPheSerThr 
 Familial 
 Maternal 
  
 GEN229R009 
 missense_variant 
 c.3142C>T 
 p.Arg1048Trp 
 Familial 
 Maternal 
 Simplex 
 GEN229R010 
 missense_variant 
 c.3380C>T 
 p.Thr1127Ile 
 Familial 
 Maternal 
  
 GEN229R011 
 missense_variant 
 c.3899C>T 
 p.Ala1300Val 
 Familial 
 Maternal 
 Multiplex 
 GEN229R012 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN229R013 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN229R014 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN229R015 
 missense_variant 
 c.1178C>T 
 p.Ala393Val 
  
  
  
 GEN229R016 
 missense_variant 
 NM_012309.3:c.1793C>A 
 p.Arg598Leu 
  
  
  
 GEN229R017 
 missense_variant 
 c.2000G>T 
 p.Gly667Val 
 Familial 
 Paternal 
 Simplex 
 GEN229R018 
 missense_variant 
 NM_012309.3:c.2187C>T 
 p.Ala729Thr 
 Familial 
 Maternal 
 Multiplex 
 GEN229R019 
 missense_variant 
 c.3484G>A 
 p.Gly1162Arg 
  
  
  
 GEN229R020 
 missense_variant 
 NM_012309.3:c.3510C>T 
 p.Gly1170Arg 
 Familial 
 Maternal 
 Simplex 
 GEN229R021 
 missense_variant 
 c.4126G>A 
 p.Val1376Ile 
  
  
  
 GEN229R022 
 missense_variant 
 c.*819A>T 
  
 Familial 
 Maternal 
 Simplex 
 GEN229R023 
 missense_variant 
 NM_012309.3:c.5165A>G 
 p.Leu1722Pro 
 Familial 
 Paternal 
 Simplex 
 GEN229R024 
 missense_variant 
 NM_012309.3:c.1229G>A 
 p.Thr410Met 
  
  
  
 GEN229R025 
 missense_variant 
 NM_012309.3:c.1670C>T 
 p.Ser557Asn 
  
  
  
 GEN229R026 
 missense_variant 
 NM_012309.3:c.5149C>T 
 p.Met1717Ile 
  
  
  
 GEN229R027 
 missense_variant 
 c.467A>G 
 p.Lys156Arg 
  
  
  
 GEN229R028 
 synonymous_variant 
 c.492G>A 
 p.Leu164= 
  
  
  
 GEN229R029 
 intron_variant 
 c.587C>T 
 p.Thr196Ile 
  
  
  
 GEN229R030 
 intron_variant 
 c.2142-15C>A 
  
  
  
  
 GEN229R031 
 intron_variant 
 c.2142-5G>T 
  
  
  
  
 GEN229R032 
 missense_variant 
 c.569G>A 
 p.Arg190His 
  
  
  
 GEN229R033 
 intron_variant 
 c.2269C>T 
 p.Leu757Phe 
  
  
  
 GEN229R034 
 intron_variant 
 c.2406-21C>T 
  
  
  
  
 GEN229R035 
 intron_variant 
 c.913-8780C>T 
  
  
  
  
 GEN229R036 
 intron_variant 
 c.2675G>C 
 p.Arg892Pro 
  
  
  
 GEN229R037 
 intron_variant 
 c.922-3220G>A 
  
  
  
  
 GEN229R038 
 intron_variant 
 c.1028+13G>A 
  
  
  
  
 GEN229R039 
 intron_variant 
 c.1148-109C>T 
  
  
  
  
 GEN229R040 
 missense_variant 
 c.1201A>C 
 p.Lys401Gln 
  
  
  
 GEN229R041 
 synonymous_variant 
 c.1284G>A 
 p.Gln428= 
  
  
  
 GEN229R042 
 intron_variant 
 c.316C>A 
 p.Pro106Thr 
  
  
  
 GEN229R043 
 intron_variant 
 c.1302+35G>A 
  
  
  
  
 GEN229R044 
 intron_variant 
 c.1100G>A 
 p.Gly367Asp 
  
  
  
 GEN229R045 
 missense_variant 
 c.1316G>A 
 p.Cys439Tyr 
  
  
  
 GEN229R046 
 synonymous_variant 
 c.1243C>A 
 p.His415Asn 
  
  
  
 GEN229R047 
 missense_variant 
 c.1763A>G 
 p.Tyr588Cys 
  
  
  
 GEN229R048 
 synonymous_variant 
 c.1923G>A 
 p.Glu641= 
  
  
  
 GEN229R049 
 synonymous_variant 
 c.1903C>T 
 p.Leu635Phe 
  
  
  
 GEN229R050 
 synonymous_variant 
 c.2823C>T 
 p.Thr941= 
  
  
  
 GEN229R051 
 synonymous_variant 
 c.2986C>T 
 p.Arg996Trp 
  
  
  
 GEN229R052 
 synonymous_variant 
 c.3324C>T 
 p.Asp1108= 
  
  
  
 GEN229R053 
 missense_variant 
 c.3471C>T 
 p.His1157= 
  
  
  
 GEN229R054 
 intron_variant 
 c.3843-12T>C 
  
  
  
  
 GEN229R055 
 frameshift_variant 
 c.1494-1167_1494-1166insGT 
  
 De novo 
 NA 
 Simplex 
 GEN229R056 
 synonymous_variant 
 c.132G>A 
 p.Pro44= 
 De novo 
 NA 
 Simplex 
 GEN229R057 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN229R058 
 inversion 
  
  
 De novo 
 NA 
 Simplex 
 GEN229R059 
 translocation 
  
  
 De novo 
 NA 
  
 GEN229R060 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN229R061 
 translocation 
  
  
 De novo 
 NA 
  
 GEN229R062 
 nonsynonymous_variant 
  
  
 Unknown 
  
 Unknown 
 GEN229R063 
 missense_variant 
 c.1313C>T 
 p.Thr438Met 
 Familial 
 Maternal 
  
 GEN229R064 
 missense_variant 
 c.3251G>T 
 p.Gly1084Val 
 Unknown 
  
  
 GEN229R065 
 missense_variant 
 c.1829C>A 
 p.Pro610His 
 Unknown 
  
  
 GEN229R066 
 missense_variant 
 c.1920A>G 
 p.Ter640= 
 Unknown 
  
  
 GEN229R067 
 missense_variant 
 c.2872C>A 
 p.Arg958Ser 
 Unknown 
  
  
 GEN229R068 
 missense_variant 
 c.3355C>A 
 p.Pro1119Thr 
 Unknown 
  
  
 GEN229R069 
 missense_variant 
 c.3431C>T 
 p.Ser1144Phe 
 Familial 
 Maternal 
  
 GEN229R070 
 missense_variant 
 c.4673G>A 
 p.Arg1558Gln 
 Familial 
 Maternal 
  
 GEN229R071 
 missense_variant 
 c.4936C>A 
 p.Leu1646Met 
 Familial 
 Maternal 
  
 GEN229R072 
 missense_variant 
 c.5191G>T 
 p.Ala1731Ser 
 Familial (n=2), unknown (n=2) 
 Maternal (n=2) 
  
 GEN229R073 
 missense_variant 
 c.1733C>T 
 p.Pro578Leu 
 Familial 
 Maternal 
 Multiplex 
 GEN229R074 
 stop_gained 
 c.757C>T 
 p.Arg253Ter 
 De novo 
 NA 
 Simplex 
 GEN229R075 
 missense_variant 
 c.3427G>A 
 p.Ala1143Thr 
 De novo 
 NA 
 Simplex 
 GEN229R076 
 frameshift_variant 
 c.*493dup 
  
 De novo 
 NA 
  
 GEN229R077 
 missense_variant 
 c.2518C>T 
 p.Pro840Ser 
 Familial 
 Paternal 
  
 GEN229R078 
 stop_gained 
 c.87C>G 
 p.Tyr29Ter 
 De novo 
 NA 
 Simplex 
 GEN229R079 
 missense_variant 
 c.359G>A 
 p.Arg120Gln 
 Familial 
 Maternal 
 Simplex 
 GEN229R080 
 frameshift_variant 
 c.*1135_*1136del 
  
 De novo 
 NA 
  
 GEN229R081 
 missense_variant 
 c.31G>A 
 p.Glu11Lys 
 Unknown 
  
 Multiplex 
 GEN229R082 
 missense_variant 
 c.1727C>T 
 p.Pro576Leu 
 Unknown 
  
  
 GEN229R083 
 stop_gained 
 c.2375C>T 
 p.Ser792Leu 
 De novo 
 NA 
 Simplex 
 GEN229R084 
 stop_gained 
 c.4203C>A 
 p.Phe1401Leu 
 De novo 
 NA 
 Simplex 
 GEN229R085 
 missense_variant 
 c.5045G>A 
 p.Arg1682His 
 De novo 
 NA 
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN229C001 
 intron_variant 
 rs76717360 
 c.2062-22283G>A;c.298-22283G>A 
  
 226 Chinese ASD cases (188 male, 38 female) and 239 Chinese controls without ASD or other psychiatric disorders (193 males, 46 females) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion
 2
 
11
Deletion
 7
 
11
Duplication
 3
 
11
Deletion-Duplication
 16
 

R_SHANK2_1_KO_HM_SCH-39166-1

Rescue Type: RESCUE-Pharmaceutical
Rescue Paradigm: ZFN targeted to exon 31 of Shank2, targeting PDZ domain, animals were treated with the dopamine D1 receptor antagonist SCH-39166 0.01 mg/kg i.p.

R_SHANK2_1_KO_HM_SCH-39166-1

Category
Entity
Effect on phenotype Qualification
Restored Treatment improves measured phenotype significantly
Refractory Treatment does not improve measured phenotype (was expected to do so)
Ameliorated Treatment provides partial correction or improvement of measured phenotype
No adverse effect Treatment does not affect the parameter adversely
Sustained effect Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Unexpected results Treats an unexpected phenotype
Side effect Exaggerates an unexpected phenotype
Experimental Paradigm
Age at Testing
Circling1
Ameliorated
Description: Decreased circling behavior compared to untreated knockout
 Open field test
 2-3 months
Reward reinforced choice behavior1
Refractory
Description: No change in breakpoint compared to untreated knockout
 Operant self-learning paradigm
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure, Sensory, Social behavior

R_SHANK2_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
 General locomotor activity: ambulatory activity1
 Increased
Description: Increased distance travelled
 Open field test
 2-3 months
 Dendritic architecture: dendritic tree complexity1
 Increased
Description: Increased dendritic brancing in striatum
 Sholl analysis
 Unreported
 Dendritic architecture: dendritic tree complexity1
 Decreased
Description: Decreased dendritic branching in hippocampus
 Sholl analysis
 Unreported
 Neuronal size1
 Increased
Description: Increased neuronal soma size in striatum
 Golgi-cox staining
 Unreported
 Neuronal size1
 Decreased
Description: Decreased neuronal soma size in hippocampus
 Golgi-cox staining
 Unreported
 Synaptic plasticity: striatal ltd1
 Increased
Description: Increase in striatal LTD response
 Field potential recordings
 Unreported
 Event related oscillations (eros) in electroencephalography (eeg)1
 Abnormal
Description: Abnormal spectral signature
 Power spectral analysis
 Unreported
 Synaptic plasticity: hippocampal ltp1
 Decreased
Description: Decreased hippocampal LTP in response to theta-burst stimulation
 Field potential recordings
 Unreported
 Synaptic plasticity: hippocampal ltd1
 Decreased
Description: Absent hippocampal LTD in response to low frequency stimulation
 Field potential recordings
 Unreported
 Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
 Increased
Description: Increase in NMDA current amplitude, with no change in AMPA current amplitude
 Field potential recordings
 Unreported
 Circling1
 Increased
Description: Increased circling behavior
 Open field test
 2-3 months
 Rearing behavior1
 Increased
Description: Increased rearing behavior
 Open field test
 2-3 months
 Social interaction: with juveniles1
 Decreased
Description: Decreased social interaction
 Reciprocal social interaction test
 2-3 months
 Juvenile play1
 Decreased
Description: Decreased juvenile play
 Reciprocal social interaction test
 5-6 weeks
 Social interaction1
 Decreased
Description: Decreased social interaction
 Reciprocal social interaction test
 2-3 months
 Social habituation1
 Decreased
Description: Decreased social habituation
 Reciprocal social interaction test
 2-3 months
 Exploratory activity1
 Decreased
Description: Decreased object exploration
 Object preference test
 2-3 months
 Cognitive flexibility: associative learning: operant self-learning1
 Decreased
Description: Decreased associative learning
 Operant self-learning paradigm
 2-3 months
 Reward reinforced choice behavior1
 Increased
Description: Increased motivational lever pressing, higher breakpoint
 Operant self-learning paradigm
 2-3 months
 Targeted expression1
 Decreased
Description: Absent protein expression
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 Unreported
 Protein localization: synapse1
 Increased
Description: Increase in mGluR1 in striatum
 Fractionation
 Unreported
 Targeted expression1
 Decreased
Description: Absent protein expression
Exp Paradigm: Western blot
 Western blot
 Unreported
Protein localization: synapse1
 No change
 Fractionation
 Unreported
Protein localization: synapse1
 No change
 Fractionation
 Unreported
Hyperactivity1
 No change
 Operant self-learning paradigm
 2-3 months
Social approach1
 No change
 Three-chamber social approach test
 2-3 months
Social memory1
 No change
 Three-chamber social approach test
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Physiological parameters, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
DNM2 dynamin 2 1785 P50570 Y2H; IP/WB; GST
Okamoto PM , et al. 2001
PDE4D phosphodiesterase 4D, cAMP-specific 5144 Q08499 IP/WB; GST
Lee JH , et al. 2007
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
GRID2 glutamate receptor, ionotropic, delta 2 14804 Q61625 Y2H; IP/WB; GST; Surface plasmon resonance (SPR)
Uemura T , et al. 2004
GRIP1 glutamate receptor interacting protein 1 74053 Q925T6 IP/WB
Uemura T , et al. 2004
Khdrbs3 KH domain containing, RNA binding, signal transduction associated 3 13992 Q9R226 RNA-Seq
Traunmller L , et al. 2016
ARHGEF7 Rho guanine nucleotide exchange factor (GEF7) 114559 O55043 Y2H; GST; IP/WB
Park E , et al. 2003
CFTR cystic fibrosis transmembrane conductance regulator homolog 12638 P26361 Y2H; IP/WB
Kim JY , et al. 2003
CTTN cortactin 60465 Q66HL2 Y2H; GST; IP/WB
Du Y , et al. 1998
DBNL Drebrin-like 13169 Q62418 GST; Far Western Blot
Qualmann B , et al. 2004
DLG4 discs, large homolog 4 (Drosophila) 29495 P31016 Y2H; IP/WB
Boeckers TM , et al. 1999
DLGAP1 discs, large (Drosophila) homolog-associated protein 1 65040 P97836 Y2H; GST; IP/WB
Naisbitt S , et al. 1999
DLGAP2 discs, large (Drosophila) homolog-associated protein 2 116681 P97837 Y2H
Boeckers TM , et al. 1999
DLGAP3 discs, large (Drosophila) homolog-associated protein 3 286923 P97838 Y2H
Boeckers TM , et al. 1999
DLGAP4 discs, large homolog-associated protein 4 (Drosophila) 286930 P97839 Y2H
Boeckers TM , et al. 1999
DYNLL1 dynein light chain LC8-type 1 58945 P63170 IP/WB
Naisbitt S , et al. 2000
DYNLL2 dynein light chain LC8-type 2 140734 Q78P75 IP/WB
Naisbitt S , et al. 2000
HOMER1 homer homolog 1 (Drosophila) 29456 Q9Z214 GST; IP/WB
Hwang JI , et al. 2005
ITPR3 inositol 1,4,5-triphosphate receptor, type 3 25679 Q63269 IP/WB
Hwang JI , et al. 2005
LPHN1 latrophilin 1 65096 O88917 Y2H; Far Western Blot; IP/WB
Kreienkamp HJ , et al. 2000
LRRC7 leucine rich repeat containing 7 117284 P70587 IP/WB; GST
Quitsch A , et al. 2005
MYO5A myosin VA 25017 Q9QYF3 IP/WB
Naisbitt S , et al. 2000
PLCB3 phospholipase C, beta 3 29322 Q99JE6 Y2H; GST; IP/WB
Hwang JI , et al. 2005
SLC4A7 solute carrier family 4, sodium bicarbonate cotransporter, member 7 117955 Q9R1N3 Y2H
Kim JY , et al. 2003
SLC9A3 solute carrier family 9 (sodium/hydrogen exchanger), member 3 24784 P26433 Y2H; IP/WB; Surface plasmon resonance (SPR)
Han W , et al. 2005
SSTR2 somatostatin receptor 2 54305 P30680 Y2H; Far Western Blot; IP/WB
Zitzer H , et al. 1999
LZTS2 leucine zipper, putative tumor suppressor 2 495421 Q5U4W1 IP/WB
Gessert S , et al. 2011

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