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.
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.
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:
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:
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:
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.
Exp Paradigm: NA
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.
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.
Exp Paradigm: NA
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
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)
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: 29
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.
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.
Description: The paired-pulse ratio of fepsp response at multiple interstimulus intervals (isis) shows a significant increase in ko slices.
Exp Paradigm: NA
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.
Exp Paradigm: NA
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.
Exp Paradigm: NA
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.
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.
Exp Paradigm: NA
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.
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)
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
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.
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)
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
