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Relevance to Autism

Rare variants in the SLC9A9 gene have been identified with autism in the HMCA cohort (Morrow et al., 2008). In addition, rare variants in SLC9A9 have been identified with ADHD and genetic association has been found with age of onset of ADHD.

Molecular Function

enzyme involved in pH regulation

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Identifying autism loci and genes by tracing recent shared ancestry.
ASD
Support
SLC9A9 Co-expression modules in autism-associated brain regions.
Support
Exonic deletion of SLC9A9 in autism with epilepsy.
ASD, epilepsy
Support
Genes for endosomal NHE6 and NHE9 are misregulated in autism brains.
ASD
Support
Effect of disease-associated SLC9A9 mutations on protein-protein interaction networks: implications for molecular mechanisms for ADHD and autism.
ASD, ADHD
Support
A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.
Highly Cited
Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like ph...
ADHD
ID
Recent Recommendation
Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.
ADHD
Recent Recommendation
Cell surface levels of organellar Na? exchanger isoform 6 are regulated by interaction with RACK1.
Recent Recommendation
Vestibular hair bundles control pH with (Na, K)/H exchangers NHE6 and NHE9.
Recent Recommendation
Functional evaluation of autism-associated mutations in NHE9.
ASD
Recent Recommendation
Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN238R001 
 inversion 
  
  
 Familial 
  
 Multiplex 
 GEN238R002 
 stop_gained 
 c.1267C>T 
 p.Arg423Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN238R003 
 missense_variant 
 c.349C>A 
 p.Pro117Thr 
 Unknown 
  
 Unknown 
 GEN238R004 
 missense_variant 
 c.526G>A 
 p.Val176Ile 
 Unknown 
  
 Unknown 
 GEN238R005 
 missense_variant 
 c.707T>C 
 p.Leu236Ser 
 Unknown 
  
 Unknown 
 GEN238R006 
 splice_site_variant 
 c.992-2A>G 
 p.? 
 Unknown 
  
 Unknown 
 GEN238R007 
 missense_variant 
 c.1485G>A 
 p.Leu495%3D 
 Unknown 
  
 Unknown 
 GEN238R008 
 splice_site_variant 
 A>G 
  
 Unknown 
  
 Unknown 
 GEN238R009 
 missense_variant 
 c.1824C>A 
 p.Asp608Glu 
 Unknown 
  
 Unknown 
 GEN238R010a 
 copy_number_loss 
  
  
 Familial 
 Both parents 
 Simplex 
 GEN238R011 
 missense_variant 
 c.1312T>C 
 p.Ser438Pro 
 Unknown 
  
 Unknown 
 GEN238R012 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multi-generational 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN238C001 
 intron_variant 
 rs13058809 
 c.534-25975A>G 
  
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
 GEN238C002 
 intergenic_variant 
 rs1992426 
  
  
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
 GEN238C003 
 intron_variant 
 rs4330252 
 c.534-30711G>A 
 N/A 
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
 GEN238C004 
 downstream_gene_variant 
 rs6414353 
  
 N/A 
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
 GEN238C005 
 intron_variant 
 rs6770565 
 c.756-16398A>G;c.108-16398A>G 
  
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
 GEN238C006 
 intron_variant 
 rs7613679 
 c.755+12312T>C;c.107+12312T>C 
 N/A 
 958 parent-offspring ADHD trios of European ancestry 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion
 1
 
3
Duplication
 1
 
3
Deletion
 1
 
3
Deletion-Duplication
 13
 

Model Summary

SLC9A9 deficient mice exhibit impaired social recognition but not social interaction, increased repetitive behaviors, and altered sensory processing together with hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues neurotransmitter release in SLC9A9 deficient mice.

References

Type
Title
Author, Year
Primary
A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

M_SLC9A9_1_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 5 of the Slc9a9 gene using Nestin-cre, in neurons and glia of the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: C57Bl/6Tn
Genetic Background: C57Bl/6
ES Cell Line: JM8A3.N1 embryonic stem (ES) cells (derived from C57Bl/6)
Mutant ES Cell Line:
Model Source:

M_SLC9A9_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Slc9a9 homozygous knocked out mice were generated by deleting exon 5 in Slc9A9 that introduces more than a dozen in-frame stop codons through the rest of the transcript.
Allele Type: knockout
Strain of Origin: C57Bl/6Tn
Genetic Background: C57Bl/6
ES Cell Line: JM8A3.N1 embryonic stem (ES) cells (derived from C57Bl/6)
Mutant ES Cell Line:
Model Source:

M_SLC9A9_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Slc9a9 heterozygous knocked out mice were generated by deleting exon 5 in Slc9A9 that introduces more than a dozen in-frame stop codons through the rest of the transcript.
Allele Type: knockout
Strain of Origin: C57Bl/6Tn
Genetic Background: C57Bl/6
ES Cell Line: JM8A3.N1 embryonic stem (ES) cells (derived from C57Bl/6)
Mutant ES Cell Line:
Model Source:

M_SLC9A9_1_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Repetitive digging1
Increased
Description: CKO mutant mice bury more marbles compared to controls.
 Marble-burying test
 Adult
Seizures1
Increased
Description: CKO mutants show tonic clonic seizures in 2 out of 100 mice.
 General observations
 Not reported
Olfaction1
Abnormal
Description: CKO mutant mice respond equivalently to non-social, social, and aversive scents whereas in wildtype controls exposure to male and female mouse odor elicits a larger response than food odorants (almond, banana) or the aversive odorant of bobcat urine.
 Olfactory discrimination test
 Adult
Allogrooming1
Decreased
Description: CKO mutants show decreased allogrooming compared to controls.
 Home cage behavior
 Adult
Social memory1
Decreased
Description: CKO mutant mice fail to habituate to a subject mouse upon repeated exposure indicating an inability to recognize the subject mouse, compared to controls that spend less time investigating a subject mouse upon repeat exposure.
 Social recognition test
 Adult
Allogrooming1
Decreased
Description: CKO mutants show decrease in allogrooming compared to controls.
 Home cage behavior
 3 weeks
Social interaction: with juveniles1
Decreased
Description: CKO mutants show decrease in close physical contact, social sniffing or following another mouse, compared to controls.
 Home cage behavior
 3 weeks
Juvenile play1
Decreased
Description: CKO mutants show decrease in soliciting play compared to controls.
Exp Paradigm: Crawling over/under, touching while pushing past, lodging under were scored as soliciting play.
 Home cage behavior
 3 weeks
Size/growth1
Decreased
Description: CKO mutants show lower body weight compared to controls.
 Body weight measurement
 4-6 months
Targeted expression1
Decreased
Description: CKO mutants show absence of SLC9A9 mRNA compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. -Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 Not reported
Targeted expression1
Decreased
Description: CKO mutants show absence of SLC9A9 mRNA compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. - Western blot
 Western blot
 Not reported
Mortality/lethality1
 No change
 Survival analysis
 Not reported
Anxiety1
 No change
 Elevated plus maze test
 Not reported
Anxiety1
 No change
 Open field test
 Not reported
Exploratory activity1
 No change
 Novel object recognition test
 Not reported
Response to novelty1
 No change
 Novel object recognition test
 Not reported
General locomotor activity1
 No change
 Cliff avoidance test
 Not reported
General locomotor activity: ambulatory activity1
 No change
 Open field test
 Not reported
Hyperactivity1
 No change
 Cliff avoidance test
 Not reported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Not reported
Olfaction1
 No change
 Buried food test
 Adult
Pain or nociception: thermal1
 No change
 Hot plate test
 Adult
Social approach1
 No change
 Three-chamber social approach test
 Adult
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters

M_SLC9A9_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Decay kinetics of evoked post synaptic currents1
Decreased
Description: KO mutants show slowing of Fluo5F-AM, calcium dye fluorescence decay post stimulus suggesting that the observed reduction in peak Ca2+ may underestimate the full extent of the defect in entry since it is compensated in part by impaired channel inactivation or reduced clearance. KO mutant neurons show no change in reduction of the peak Ca2+ response to paired-pulse stimulation as in response to a single action potential, no change in the rate of decay, and normal facilitation of response to the second stimulus relative to the first.
Exp Paradigm: Ca2+ entry was investigated using the low affinity calcium indicator dye Fluo5F-AM and presynaptic boutons were identified with the red-shifted styryl dye FM4-64. Stimulation was performed at 10 Hz for 60 s.
 Immunofluorescence staining
 Adult
Presynaptic function: vesicle recycling1
Decreased
Description: KO mutants show decreased synaptic vesicle exocytosis compared to controls.
 Immunofluorescence staining
 Adult
Miniature post synaptic current amplitude: inhibitory1
Decreased
Description: KO mutants show a reduction in mIPSC amplitude compared to controls.
 Whole-cell patch clamp
 Adult
Presynaptic function: paired-pulse facilitation1
Increased
Description: Whole cell recording of evoked EPSCs from pyramidal neurons in CA1 shows increased PPR at 50 ms ISI in KO slices.
 Whole-cell patch clamp
 Adult
Local field potential1
Decreased
Description: In acute hippocampal slices, KO mutants show a small but significant reduction relative to WT in field excitatory postsynaptic potentials (fEPSPs) normalized to the axonal fiber volley, compared to controls.
Exp Paradigm: Synapses formed by Schaffer collaterals in stratum radiatum of hippocampal region CA1, where both presynaptic CA3 and postsynaptic CA1 pyramidal cells express NHE9 were examined.
 In vivo local field potential (lfp) recordings
 Adult
Presynaptic function: paired-pulse facilitation1
Increased
Description: The paired-pulse ratio of fEPSP response at multiple interstimulus intervals (ISIs) shows a significant increase in KO slices.
 Whole-cell patch clamp
 Adult
Ion influx and permeability: calcium1
Decreased
Description: KO mutants show impaired calcium signal upon imaging the response to a single action potential with FluoF, compared to controls. KO mutants show no change in Ca+2 influx into the neuron compared to controls when P and Q type calcium channels were blocked. KO mutants show no change in Ca+2 influx into the neuron compared to controls when N type calcium channels were blocked.
Exp Paradigm: -Agatoxin TK was used to selectively block P-type and Q-type Ca2+ channels. -conotoxin GVIA was used to inhibit N-type channels.
 Immunofluorescence staining
 Adult
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Increased
Description: KO mutants show a decrease in AMPA/NMDA dependent synaptic transmission ratios compared to controls.
 Whole-cell patch clamp
 Adult
Miniature post synaptic current frequency: excitatory1
Increased
Description: KO mice show increased mEPSC frequency compared to controls.
 Whole-cell patch clamp
 Adult
Repetitive digging1
Increased
Description: KO mutant mice bury more marbles compared to controls.
 Marble-burying test
 Adult
Seizures1
Increased
Description: Homozygote mutants show epilepsy compared to controls.
 General observations
 Not reported
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: KO mutants show recurrent bouts of high-voltage spike activity compared to controls. KO mutants show seizure bouts are characterized by an increase in low-frequency activity (<20Hz) and concomitant decrease in higher frequency (>30 Hz) activity compared to controls.
 Electroencephalogram (eeg)
 Adult
Pain or nociception: thermal1
Decreased
Description: KO mutant mice show decrease threshold of response to painful heat compared to controls.
 Hot plate test
 Adult
Olfaction1
Abnormal
Description: KO mutant mice respond more to some food odorants (banana) but not others (almond) compared to controls. KO mutant mice respond equivalently to male and female mouse odors compared to controls. KO mutant mice respond more to the aversive odorant of bobcat urine compared to controls.
 Olfactory discrimination test
 Adult
Allogrooming1
Decreased
Description: KO mutants show decrease in allogrooming compared to controls.
 Home cage behavior
 3 weeks
Social memory1
Decreased
Description: KO mutant mice fail to habituate to a subject mouse upon repeated exposure indicating an inability to recognize the subject mouse, compared to controls that spend less time investigating a subject mouse upon repeat exposure.
 Social recognition test
 Adult
Juvenile play1
Decreased
Description: KO mutants show decrease in soliciting play compared to controls.
Exp Paradigm: Crawling over/under, touching while pushing past, lodging under were scored as soliciting play.
 Home cage behavior
 3 weeks
Mortality/lethality1
Increased
Description: Homozygote mutants show early lethality compared to controls.
 General observations
 Not reported
Targeted expression1
Decreased
Description: Homozygote mutants show absence of SLC9A9 transcript and protein compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. -Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 Not reported
Targeted expression1
Decreased
Description: Homozygote mutants show absence of SLC9A9 transcript and protein compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. - Western blot
 Western blot
 Not reported
Calcium ion uptake1
Decreased
Description: KO mutants show smaller increase in bouton Ca2+ compared to controls. KO mutants show a decrease in peak Ca2+ response to one action potential, but in contrast to the trains, no change in decay compared to controls.
Exp Paradigm: Ca2+ entry was investigated using the low affinity calcium indicator dye Fluo5F-AM and presynaptic boutons were identified with the red-shifted styryl dye FM4-64. Stimulation was performed at 10 Hz for 60 s. Fluo5F was also used to image boutons in response to single action potentials.
 Immunofluorescence staining
 Adult
Size/growth1
 No change
 Body weight measurement
 4-6 months
Metabolite levels: neurometabolites1
 No change
 Immunofluorescence staining
 Adult
Protein expression level evidence1
 No change
 Western blot
 3 weeks
Protein expression level evidence1
 No change
 Western blot
 Adult
Brain cytoarchitecture1
 No change
 Histology
 Adult
Dendritic architecture: dendritic tree complexity1
 No change
 Golgi-cox staining
 Adult
Dendritic architecture: spine density1
 No change
 Golgi-cox staining
 Adult
Dendritic architecture: spine morphology1
 No change
 Golgi-cox staining
 Adult
Neuroreceptor levels: glutamate receptors: ampa receptors1
 No change
 Western blot
 Adult
Neuroreceptor levels: glutamate receptors: nmda receptors1
 No change
 Western blot
 Adult
Synapse density1
 No change
 Histology
 Adult
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 Adult
Miniature post synaptic current frequency: inhibitory1
 No change
 Whole-cell patch clamp
 Adult
Neuronal ion channel activity1
 No change
 Western blot
 Adult
Neurotransmitter metabolism: reuptake: gaba1
 No change
 Immunostaining
 Adult
Neurotransmitter metabolism: reuptake: glutamate1
 No change
 Immunostaining
 Adult
Allogrooming1
 No change
 Home cage behavior
 Adult
Social interaction: with juveniles1
 No change
 Home cage behavior
 3 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Physiological parameters

M_SLC9A9_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Juvenile play1
Decreased
Description: Heterozygous mutants show decrease in soliciting play compared to controls.
Exp Paradigm: Crawling over/under, touching while pushing past, lodging under were scored as soliciting play.
 Home cage behavior
 3 weeks
Allogrooming1
Decreased
Description: Heterozygous mutants show decrease in allogrooming compared to controls.
 Home cage behavior
 3 weeks
Targeted expression1
Decreased
Description: Heterozygote mutants show SLC9A9 mRNA reduction by 50% compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. - Western blot
 Western blot
 Not reported
Targeted expression1
Decreased
Description: Heterozygote mutants show SLC9A9 mRNA reduction by 50% compared to controls.
Exp Paradigm: The antibodies recognize the mouse protein over-expressed in heterologous cells, but fail to detect a specific signal in brain extracts from wild-type mice that is not also present in the SLC9A9 cKO. Endogenous SLC9A9 occurs at levels too low to detect. -Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 Not reported
Size/growth1
 No change
 Body weight measurement
 4-6 months
Anxiety1
 No change
 Elevated plus maze test
 Not reported
Anxiety1
 No change
 Open field test
 Not reported
Exploratory activity1
 No change
 Novel object recognition test
 Not reported
Response to novelty1
 No change
 Novel object recognition test
 Not reported
General locomotor activity1
 No change
 Cliff avoidance test
 Not reported
General locomotor activity: ambulatory activity1
 No change
 Open field test
 Not reported
Hyperactivity1
 No change
 Cliff avoidance test
 Not reported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Not reported
Repetitive digging1
 No change
 Marble-burying test
 Adult
Olfaction1
 No change
 Olfactory discrimination test
 Adult
Olfaction1
 No change
 Buried food test
 Adult
Social approach1
 No change
 Three-chamber social approach test
 Adult
Social interaction: with juveniles1
 No change
 Home cage behavior
 3 weeks
Social memory1
 No change
 Social recognition test
 Adult
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
GNB2L1 guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1 10399 P63244 Y2H; Affinity chromatography; IP/WB
Ohgaki R , et al. 2007
CHP calcineurin-like EF-hand protein 1 64152 P61023 IP; WB
Zhang-James Y , et al. 2011
RACK1 guanine nucleotide binding protein (G protein), beta polypeptide 2 like 1 83427 P63245 IP; WB
Zhang-James Y , et al. 2011

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