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Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, studies have found SLC9A6 variants to be identified with X-linked mental retardation and Angelman-like phenotypes. As well, mutation in the SLC9A6 gene has been identified with autism (Garbern et al., 2010).

Molecular Function

This gene encodes a sodium-hydrogen exchanger that is a member of the solute carrier family 9. The encoded protein may be involved in regulating endosomal pH and volume.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.
Christianson syndrome
ASD, ID, epilepsy, dystonia
Support
A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.
Christianson syndrome
Support
The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing
ASD, ID
Support
Large-scale discovery of novel genetic causes of developmental disorders.
ID
Microcephaly
Support
Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.
ID
Support
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
ID
Support
A Christianson syndrome-linked deletion mutation (287ES288) in SLC9A6 impairs hippocampal neuronal plasticity.
Christianson syndrome
Support
Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.
Christianson syndrome
ID, epilepsy, ASD
Support
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.
ASD, DD, epilepsy/seizures
Support
Genes for endosomal NHE6 and NHE9 are misregulated in autism brains.
ASD
Support
Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.
Microcephaly
DD, epilepsy/seizures
Support
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Epilepsy/seizures
DD/ID
Support
Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression
ASD
Developmental regression, epilepsy/seizures
Highly Cited
SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.
X-linked mental retardation syndrome
Recent Recommendation
Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.
Recent Recommendation
Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.
Christianson syndrome
ID, Epilepsy
Recent Recommendation
The Na? exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.
Recent Recommendation
Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome.
Angelman-like syndrome

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN237R001 
 inframe_deletion 
 c.764_769del 
 p.Phe255_Ala257delinsSer 
 Familial 
 Maternal 
 Multiplex 
 GEN237R002 
 stop_gained 
 c.1402C>T 
 p.Leu468Phe 
 Familial 
 Maternal 
 Simplex 
 GEN237R003 
 splice_site_variant 
 c.509del 
 p.Asn170MetfsTer30 
 Familial 
 Maternal 
 Multiplex 
 GEN237R004 
 frameshift_variant 
 c.513_514del 
 p.Glu171AspfsTer3 
 Familial 
 Maternal 
 Multiplex 
 GEN237R005 
 missense_variant 
 c.25G>T 
 p.Ala9Ser 
 Familial 
 Maternal 
  
 GEN237R006 
 intron_variant 
 c.1462+8G>A 
  
  
  
  
 GEN237R007 
 intron_variant 
  
 p.(=) 
  
  
  
 GEN237R008 
 inframe_deletion 
 c.1012_1020del 
 p.Gly338_Ala340del 
 Familial 
 Maternal 
 Multi-generational 
 GEN237R009 
 stop_gained 
 c.916C>T 
 p.Gln306Ter 
  
  
 Simplex 
 GEN237R010 
 splice_site_variant 
 c.1148-2A>G 
  
 Familial 
 Maternal 
 Simplex 
 GEN237R011 
 splice_site_variant 
 c.526-9_526-5del 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN237R012 
 missense_variant 
 c.1148G>A 
 p.Gly383Asp 
 De novo 
 NA 
 Simplex 
 GEN237R013 
 frameshift_variant 
 c.1570dup 
 p.Val524GlyfsTer20 
 De novo 
 NA 
 Simplex 
 GEN237R014 
 stop_gained 
 c.1710G>A 
 p.Trp570Ter 
 De novo 
 NA 
 Simplex 
 GEN237R015 
 stop_gained 
 c.1568G>A 
 p.Trp523Ter 
 De novo 
 NA 
 Simplex 
 GEN237R016 
 frameshift_variant 
 c.697_704dup 
 p.Leu236ValfsTer2 
 De novo 
 NA 
 Simplex 
 GEN237R017 
 splice_site_variant 
 c.681G>A 
 p.Gly227= 
 De novo 
 NA 
 Simplex 
 GEN237R018 
 stop_gained 
 c.1710G>A 
 p.Trp570Ter 
 De novo 
 NA 
 Simplex 
 GEN237R019 
 stop_gained 
 c.190G>T 
 p.Glu64Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN237R020 
 stop_gained 
 c.1498C>T 
 p.Arg500Ter 
 Familial 
 Maternal 
 Simplex 
 GEN237R021 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN237R022 
 stop_gained 
 c.1639G>T 
 p.Glu547Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN237R023 
 stop_gained 
 c.1498C>T 
 p.Arg500Ter 
 Familial 
 Maternal 
 Simplex 
 GEN237R024 
 stop_gained 
 c.1498C>T 
 p.Arg500Ter 
 Familial 
 Maternal 
 Simplex 
 GEN237R025 
 frameshift_variant 
 c.615dup 
 p.Arg206SerfsTer58 
 Familial 
 Maternal 
  
 GEN237R026 
 stop_gained 
 c.616C>T 
 p.Arg206Ter 
  
  
  
 GEN237R027 
 missense_variant 
 c.316A>G 
 p.Met106Val 
 Familial 
 Maternal 
 Multi-generational 
 GEN237R028 
 missense_variant 
 c.286G>A 
 p.Ala96Thr 
 Familial 
 Maternal 
  
 GEN237R029 
 missense_variant 
 c.171C>G 
 p.Ile57Met 
 Unknown 
  
 Unknown 
 GEN237R030 
 missense_variant 
 c.1777C>G 
 p.Leu593Val 
 Unknown 
  
 Unknown 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 18
 
X
Deletion
 2
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 1
 
X
Deletion-Duplication
 12
 

Model Summary

Slc9a6 null mice have dendritic abnormalities with decrease in synapse numbers.

References

Type
Title
Author, Year
Additional
X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction.
Primary
Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.
Additional
X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalit...

M_SLC9A6_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A lacZ cassette was inserted in exon 6 to inactivate the Slc9a6 gene, the endogenous gene promoter drives the expression of beta-galactosidase. Maintained in the mixed background, and maybe male or (-/y) or female (-/-) mice as Slc9a6 is on the X chromosome.
Allele Type: Targeted (knocout, reporter)
Strain of Origin: 129P2/OlaHsd
Genetic Background: 129P2/OlaHsd*C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: JAX

M_SLC9A6_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A lacZ cassette was inserted to inactivate the Slc9a6 gene in exon6, the endogenous gene promoter drives the expression of beta-galactosidase. This line is bred to a pure C57bl/6 background.
Allele Type: Targeted (knocout, reporter)
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: JAX

M_SLC9A6_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: A lacZ cassette was inserted in exon 6 to inactivate the Slc9a6 gene, the endogenous gene promoter drives the expression of beta-galactosidase. Maintained in the mixed background and are female (-/+) mice as Slc9a6 is on the X chromosome.
Allele Type: Targeted (knocout, reporter)
Strain of Origin: 129P2/OlaHsd
Genetic Background: 129P2/OlaHsd*C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: JAX

M_SLC9A6_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hyperactivity2
Increased
Description: Slc9a6 null males have a longer distance traveled and increased number of rears compared to wild type controls, indicating increase hyperactivity
Exp Paradigm: Males
 Open field test
 8-8.5 months
Ataxia2
Increased
Description: Slc9a6 null males have increased ataxia compared to controls and even het female mice
Exp Paradigm: Males
 General observations
 8-8.5 months
Motor coordination and balance1
Decreased
Description: Slc9a6 null male mice have reduced motor coordination and balance in the balance beam test, determined by increased latency to cross beam and increased number of slips
Exp Paradigm: NA
 Balance beam test
 Adult
Hyperactivity1
Increased
Description: Slc9a6 null males have increased levels of hyperactivity in the open field test determined by increased distance traveled and number of rears
Exp Paradigm: Males
 Open field test
 Adult
Neuronal number: purkinje cells2
Decreased
Description: A significant loss of purkinje cells is seen in the anterior and posterior zones of the cerebellum, mostly in lobule i-ii
Exp Paradigm: Males
 Immunohistochemistry
 8 months
Neuronal number: purkinje cells1
Decreased
Description: There is a significant loss of purkinje cells in the cerebellum, occurring in a patterned manner in the vermis and hemispheres
Exp Paradigm: Males
 Immunohistochemistry
 P19, 8 weeks, 5 months
Lysosomal function: neuronal1
Decreased
Description: Slc9a6 null male and female mice have a significant accumulation of the gm2 ganglioside in neurons from the ca3/ca4 region and the dentate gyrus of the hippocampus as well as the hypothalamus, fasciola cinereum and piriform cortex
Exp Paradigm: Males and females
 Immunohistochemistry
 3 months
Lysosomal function: neuronal1
Decreased
Description: Slc9a6 null female mice have significant accumulation of the gm2 ganglioside in the neurons of the basolateral amygdala starting at 8 weeks itself
Exp Paradigm: Females
 Immunohistochemistry
 8 weeks
Lysosomal function: neuronal2
Decreased
Description: Accumulation of gm2 ganglioside inside neurons from various parts of the brain, including the amygdala and ca3/ca4 hippocampal regions indicate significant dysfunction of the lysosomal degradation pathway for plasma membrane -attached lipids, in slc9a6 null male mice as well
Exp Paradigm: Males
 Immunohistochemistry
 4 weeks, 8-8.5 months
Astrogliosis2
Increased
Description: The cerebella of slc9a6 null males show increased gliosis in the molecular layer in the anterior and posterior zones
Exp Paradigm: NA
 NA
 8-8.5 months
Spatial reference memory2
Decreased
Description: Slc9a6 null males show no preference to the change in position of a previously encountered object
Exp Paradigm: NA
 Object-place recognition test
 5-5.5 months
Spatial reference memory1
Decreased
Description: Slc9a6 null males show no preference to the change in position of a previously encountered object
Exp Paradigm: Males
 Object-place recognition test
 Adult
Protein aggregation: neuronal1
Increased
Description: There is an increase in the accumulation of hyperphosphorylated tau protein in the soluble fraction of the brain
Exp Paradigm: Males and females
 Western blot
 NA
Enzyme activity1
Decreased
Description: The hexosaminidase assay for beta hexosaminidase, the enzyme that degrades gm2 ganglioside conducted on brain tissue showed an absolute lack of enzyme activity in slc9a6 null mice
Exp Paradigm: NA
 Hexosaminidase assay
 NA
Anxiety2
 No change
 Open field test
 8-8.5 months
Neuronal number1
 No change
 Microscopic analysis
 P19, 8 weeks, 5 months
Seizures1
 No change
 NA
 NA
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Molecular profile, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_SLC9A6_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic morphology1
Decreased
Description: The number of synapses was reduced in slc9a6 null mice. they also had reduced number of mature synapses, both in basal dendrites and apical dendrites
Exp Paradigm: Golgi-cox stain was used to stain the hippocampus and the cortex
 Immunohistochemistry
 3 weeks
Dendritic architecture: spine density1
Decreased
Description: Dendritic branching points and total number of branches are reduced in slc9a6 null mice, in the ca3 and ca1 regions of the hippocampus, compared to littermate controls
Exp Paradigm: Golgi-cox stain was used to stain the hippocampus and the cortex
 Immunohistochemistry
 3 weeks
Synaptic transmission1
Decreased
Description: Slc9a6 null mice show reduced epsp
Exp Paradigm: NA
 Field potential recordings
 Unreported
Presynaptic function: presynaptic fiber volley1
Decreased
Description: There is a significant (~25%) decrease in fiber volley amplitude in the hippocampal slices from slc9a6 null mice.
Exp Paradigm: Amplitude of the fiber volley was measured in the presence of ampar inhibitor
 Field potential recordings
 Unreported
Mortality/lethality1
Abnormal
Description: There was an inconsistent increase in unexplained mortality in the first month of life in slc9a6 null mice (~10-20%)
Exp Paradigm: NA
 Survival analysis
 1 month
Presynaptic function: paired-pulse facilitation1
 No change
 NA
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_SLC9A6_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance1
Decreased
Description: Slc9a6 null male mice have reduced motor coordination and balance in the balance beam test
Exp Paradigm: Males
 Balance beam test
 8-8.5 months
Motor coordination and balance1
Decreased
Description: Slc9a6 het females have reduced motor coordination and balance
Exp Paradigm: Females
 Balance beam test
 8-8.5 months
Neuronal number: purkinje cells1
Decreased
Description: There is a significant reduction in the total number of purkinje cells in the cerebellum of slc9a6 het female mice (but it is significantly less than what is observed in males)
Exp Paradigm: Females
 Immunohistochemistry
 8 months
Lysosomal function: neuronal1
Decreased
Description: Accumulation of gm2 ganglioside inside neurons from various parts of the brain, including the amygdala and ca3/ca4 hippocampal regions indicate significant dysfunction of the lysosomal degradation pathway for plasma membrane -attached lipids, in slc9a6 het female mice
Exp Paradigm: Females
 Immunohistochemistry
 4 weeks, 8-8.5 months
Spatial reference memory1
Decreased
Description: Slc9a6 het females show no preference to the change in position of a previously encountered object, unlike wild type controls
Exp Paradigm: NA
 Object-place recognition test
 5-5.5 months
Anxiety1
 No change
 Open field test
 8-8.5 months
Ataxia1
 No change
 General observations
 8-8.5 months
Hyperactivity1
 No change
 Open field test
 8-8.5 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Molecular profile, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ALDH3A2 aldehyde dehydrogenase 3 family, member A2 224 P51648 IP; LC-MS/MS
Huttlin EL , et al. 2015
ALDH3B1 aldehyde dehydrogenase 3 family, member B1 221 P43353 IP; LC-MS/MS
Huttlin EL , et al. 2015
C3ORF39 glycosyltransferase-like domain containing 2 84892 Q8NAT1 IP; LC-MS/MS
Huttlin EL , et al. 2015
C6ORF170 chromosome 6 open reading frame 170 221322 Q96NH3 IP; LC-MS/MS
Huttlin EL , et al. 2015
C7ORF44 cytochrome c oxidase assembly factor 1 homolog (S. cerevisiae) 55744 Q9GZY4 IP; LC-MS/MS
Huttlin EL , et al. 2015
CDK20 Cyclin-dependent kinase 20 23552 Q8IZL9 IP; LC-MS/MS
Huttlin EL , et al. 2015
DNAJC30 DnaJ homolog subfamily C member 30 84277 Q96LL9 IP; LC-MS/MS
Huttlin EL , et al. 2015
ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R) 1994 Q15717 RNP IP
Abdelmohsen K , et al. 2009
FGFR2 fibroblast growth factor receptor 2 2263 P21802 IP; LC-MS/MS
Huttlin EL , et al. 2015
FKRP fukutin related protein 79147 Q9H9S5 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
FNDC4 Fibronectin type III domain-containing protein 4 64838 Q9H6D8 IP; LC-MS/MS
Huttlin EL , et al. 2015
FUT8 fucosyltransferase 8 (alpha (1,6) fucosyltransferase) 2530 B4DFS7 IP; LC-MS/MS
Huttlin EL , et al. 2015
IFNGR1 interferon gamma receptor 1 3459 P15260 IP; LC-MS/MS
Huttlin EL , et al. 2015
LGALS3 Galectin-3 3958 P17931 IP; LC-MS/MS
Huttlin EL , et al. 2015
LGALS8 Galectin-8 3964 O00214 IP; LC-MS/MS
Huttlin EL , et al. 2015
MAP1LC3B2 Microtubule-associated proteins 1A/1B light chain 3 beta 2 643246 A6NCE7 IP; LC-MS/MS
Huttlin EL , et al. 2015
MBLAC2 Metallo-beta-lactamase domain-containing protein 2 153364 Q68D91 IP; LC-MS/MS
Huttlin EL , et al. 2015
PLD6 phospholipase D family, member 6 201164 Q8N2A8 IP; LC-MS/MS
Huttlin EL , et al. 2015
RAC3 ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) 5881 P60763 IP; LC-MS/MS
Huttlin EL , et al. 2015
RELL2 RELT-like protein 2 285613 Q8NC24 IP; LC-MS/MS
Huttlin EL , et al. 2015
SERINC1 serine incorporator 1 57515 Q9NRX5 IP; LC-MS/MS
Huttlin EL , et al. 2015
SLC19A2 solute carrier family 19 (thiamine transporter), member 2 10560 O60779 IP; LC-MS/MS
Huttlin EL , et al. 2015
SLC22A9 Solute carrier family 22 member 9 114571 Q8IVM8 IP; LC-MS/MS
Huttlin EL , et al. 2015
SLC39A8 solute carrier family 39 (zinc transporter), member 8 64116 Q9C0K1 IP; LC-MS/MS
Huttlin EL , et al. 2015
SLC9A7 solute carrier family 9, subfamily A (NHE7, cation proton antiporter 7), member 7 84679 Q96T83 IP; LC-MS/MS
Huttlin EL , et al. 2015
TMEM164 transmembrane protein 164 84187 Q5U3C3 IP; LC-MS/MS
Huttlin EL , et al. 2015
TMEM87A transmembrane protein 87A 25963 Q8NBN3 IP; LC-MS/MS
Huttlin EL , et al. 2015
UBC ubiquitin C 7316 P63279 LC-MS/MS
Denis NJ , et al. 2007
YIPF3 Yip1 domain family, member 3 25844 Q9GZM5 IP; LC-MS/MS
Huttlin EL , et al. 2015

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