SLC9A6

Summary

SLC9A6 (solute carrier family 9 member A6, HGNC:11079) is a protein-coding gene on chromosome Xq26.3, encoding Sodium/hydrogen exchanger 6 (Q92581). Endosomal Na(+), K(+)/H(+) antiporter. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10479 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Christianson syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 716 total — 48 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 92
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001379110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11079
Approved symbol	SLC9A6
Name	solute carrier family 9 member A6
Location	Xq26.3
Locus type	gene with protein product
Status	Approved
Aliases	NHE6, KIAA0267, NHE-6
Ensembl gene	ENSG00000198689
Ensembl biotype	protein_coding
OMIM	300231
Entrez	10479

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 15 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000370695, ENST00000370698, ENST00000370701, ENST00000626147, ENST00000627534, ENST00000630721, ENST00000636092, ENST00000636206, ENST00000636347, ENST00000636625, ENST00000636798, ENST00000637195, ENST00000637234, ENST00000637581, ENST00000638078, ENST00000643775, ENST00000674809, ENST00000675550, ENST00000675856, ENST00000676043, ENST00000676233, ENST00000678163, ENST00000964988, ENST00000964989

RefSeq mRNA: 10 — MANE Select: NM_001379110 NM_001042537, NM_001177651, NM_001330652, NM_001379110, NM_001400909, NM_001400910, NM_001400911, NM_001400912, NM_001400913, NM_006359

CCDS: CCDS14654, CCDS44003, CCDS55504, CCDS83492, CCDS94676

Canonical transcript exons

ENST00000630721 — 18 exons

Exon	Start	End
ENSE00001434602	135998856	135998968
ENSE00001434749	135998482	135998558
ENSE00001434965	136013349	136013437
ENSE00001435595	136012949	136013054
ENSE00001435636	136010442	136010583
ENSE00001435810	136033414	136033493
ENSE00001436094	135998108	135998185
ENSE00001436361	136022586	136022697
ENSE00001436394	136040076	136040181
ENSE00001436564	136016645	136016758
ENSE00001436675	136030132	136030162
ENSE00001453392	135994786	135994985
ENSE00001453393	135985603	135985827
ENSE00001615080	136002108	136002213
ENSE00001643636	136024330	136024483
ENSE00003771725	136044452	136047269
ENSE00003775258	136028886	136028975
ENSE00003823195	135985435	135985477

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.2348 / max 101.8480, expressed in 1692 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197644	3.8481	1587
197645	1.2247	645
197646	0.0823	23
209825	0.0798	36

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.05	gold quality
middle temporal gyrus	UBERON:0002771	98.91	gold quality
pons	UBERON:0000988	98.88	gold quality
substantia nigra pars compacta	UBERON:0001965	98.84	gold quality
postcentral gyrus	UBERON:0002581	98.83	gold quality
parietal lobe	UBERON:0001872	98.73	gold quality
superior vestibular nucleus	UBERON:0007227	98.60	gold quality
orbitofrontal cortex	UBERON:0004167	98.48	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.31	gold quality
superior frontal gyrus	UBERON:0002661	98.28	gold quality
entorhinal cortex	UBERON:0002728	98.24	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.93	gold quality
CA1 field of hippocampus	UBERON:0003881	97.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.87	gold quality
medulla oblongata	UBERON:0001896	97.57	gold quality
secondary oocyte	CL:0000655	97.27	gold quality
ventral tegmental area	UBERON:0002691	96.68	gold quality
lateral globus pallidus	UBERON:0002476	96.60	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.54	gold quality
frontal pole	UBERON:0002795	96.43	gold quality
inferior olivary complex	UBERON:0002127	96.00	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.70	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.68	gold quality
dorsal root ganglion	UBERON:0000044	95.39	gold quality
occipital lobe	UBERON:0002021	95.34	gold quality
nucleus accumbens	UBERON:0001882	95.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.23	gold quality
oocyte	CL:0000023	95.18	gold quality
prefrontal cortex	UBERON:0000451	95.11	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6058	no	317.14
E-GEOD-75140	no	303.86
E-MTAB-7249	no	99.18
E-ANND-3	no	5.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

175 targeting SLC9A6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 28)

• results suggest that NHE6 is an endosomal Na(+)/H(+) exchanger that may regulate intravesicular pH and volume and contribute to lysosomal biogenesis (PMID:11940519)
• distribution of NHE6 between endosomes and plasma membrane is regulated by RACK1 (PMID:18057008)
• Mutations in SLC9A6 cause X-linked mental retardation;males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations. (PMID:18342287)
• NHE6 participates in regulation of endosomal pH and provides a basis for understanding loss of NHE6 function leading to a phenotype resembling Angelman syndrome. (PMID:19619532)
• NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells (PMID:20130086)
• NHE6 with alanine substitutions in the membrane-proximal region exhibited no apparent change in localization. (PMID:20364249)
• Analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. (PMID:20395263)
• This review defines NHE6-9 as organellar NHEs that are fairly dynamic, implying that they are subjected to intracellular trafficking and thus they continuously shuttle between organelles and the plasma membrane. (PMID:21171650)
• In mineralizing osteoblasts, slightly basic basal intracellular pH is maintained, and external acid load is dissipated, by high-capacity Na(+) /H(+) exchange via NHE1 and NHE6. (PMID:21413028)
• The involvement of SLC9A6 mutations in 22 males initially suspected to have Angelman syndrome (AS) but found on genetic testing not to have AS (AS-like cohort), and 104 male patients with X-linked mental retardation (XMR) (XMR cohort), was investigated. (PMID:21812100)
• These observations suggest that NHE6 regulates clathrin-dependent endocytosis of transferrin via pH regulation. (PMID:21881004)
• We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation in SLC9A6 (PMID:22541666)
• Data indicate SLC9A6 mutations and the clinical uniformity of male patients with Christianson syndrome in two familieis. (PMID:22931061)
• find interesting gene expression changes in endosomal NHE6 and NHE9 in postmortem autism brains. (PMID:23508127)
• This study demonistrated that Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. (PMID:25044251)
• Data show that co-expression with sodium-hydrogen antiporter NHE6 or treatment with the Na(+)/H(+) ionophore monensin shifted amyloid precursor protein (APP) away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. (PMID:25561733)
• Epileptic encephalopathy related to mutations in the SLC9A6 genes. (PMID:25818041)
• We describe a large extended family with three affected males, four carrier females, one presumed carrier female and one obligate carrier female with a c.190G>T, p.E64X mutation known to cause a premature stop codon in SLC9A6 (PMID:27142213)
• by sequencing panels of genes in patients with no precise clinical diagnosis, NGS can broaden the clinical variability associated with a known gene. We also argue that SLC9A6 gene mutations in females could be responsible for a monogenic cause of mild learning disability/constitutive speech disorders. (PMID:27256868)
• membrane trafficking of the ES mutant in SLC9A6was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death (PMID:27590723)
• NHE6 role in the neoplasm chemoresistance.NHE6 transport from endosomes to the plasma membrane triggers endosome hyperacidification. (PMID:28635961)
• Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome. (PMID:32277048)
• SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses. (PMID:33372133)
• Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome. (PMID:37381736)
• Targeting NHE6 gene expression identifies lysosome and neurodevelopmental mechanisms in a haploid in vitro cell model. (PMID:37747131)
• Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability. (PMID:37794328)
• Genes for endosomal pH regulators NHE6 and NHE9 are dysregulated in the substantia nigra in Parkinson’s disease. (PMID:38945311)
• A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD. (PMID:39107881)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc9a6a	ENSDARG00000009209
danio_rerio	slc9a6b	ENSDARG00000075382
mus_musculus	Slc9a6	ENSMUSG00000060681
rattus_norvegicus	Slc9a6	ENSRNOG00000000879
caenorhabditis_elegans		WBGENE00003730
caenorhabditis_elegans		WBGENE00003734

Paralogs (10): SLC9A7 (ENSG00000065923), SLC9A3 (ENSG00000066230), SLC9A1 (ENSG00000090020), SLC9A2 (ENSG00000115616), SLC9A5 (ENSG00000135740), SLC9C2 (ENSG00000162753), SLC9C1 (ENSG00000172139), SLC9A4 (ENSG00000180251), SLC9A9 (ENSG00000181804), SLC9A8 (ENSG00000197818)

Protein

Protein identifiers

Sodium/hydrogen exchanger 6 — Q92581 (reviewed: Q92581)

Alternative names: Na(+)/H(+) exchanger 6, Solute carrier family 9 member 6

All UniProt accessions (8): A0A0D9SFM4, A0A0D9SGH0, A0A1B0GTT2, A0A1B0GV11, A0A6Q8PFS7, A0A6Q8PGY5, A0A7I2V2B0, Q92581

UniProt curated annotations — full annotation on UniProt →

Function. Endosomal Na(+), K(+)/H(+) antiporter. Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+). By facilitating proton efflux, SLC9A6 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Responsible for alkalizing and maintaining the endosomal pH, and consequently in, e.g., endosome maturation and trafficking of recycling endosomal cargo. Plays a critical role during neurodevelopment by regulating synaptic development and plasticity. Implicated in the maintenance of cell polarity in a manner that is dependent on its ability to modulate intravesicular pH. Regulates intracellular pH in some specialized cells, osteoclasts and stereocilia where this transporter localizes to the plasma membrane.

Subunit / interactions. Homodimer. Interacts with RACK1; regulates the distribution of SLC9A6 between endosomes and the plasma membrane.

Subcellular location. Endosome membrane. Recycling endosome membrane. Early endosome membrane. Late endosome membrane. Cell membrane.

Tissue specificity. Ubiquitous. High expression in brain, skeletal muscle, and heart, but is also detected at lower levels in most other tissues.

Post-translational modifications. Ubiquitinated (in vitro). Glycosylated.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Christianson type (MRXSCH) [MIM:300243] A syndrome characterized by profound intellectual disability, epilepsy, ataxia, and microcephaly. It shows phenotypic overlap with Angelman syndrome. The disease is caused by variants affecting the gene represented in this entry. Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement (NDPACX) [MIM:301142] An X-linked dominant disorder restricted to females and characterized by parkinsonism, mild to moderate intellectual disability, cognitive decline, and psychiatric abnormalities. Disease onset is in mid-to-late adulthood, although some affected females show learning difficulties earlier in life. Brain imaging may show cerebral or cerebellar atrophy. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92581-2	2, NHE6.1, NHE6v1	yes
Q92581-1	1, NHE6.0
Q92581-3	3

RefSeq proteins (10): NP_001036002, NP_001171122, NP_001317581, NP_001366039, NP_001387838, NP_001387839, NP_001387840, NP_001387841, NP_001387842, NP_006350 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002090	NHE-6/7/9	Family
IPR004709	NaH_exchanger	Family
IPR006153	Cation/H_exchanger_TM	Domain
IPR018422	Cation/H_exchanger_CPA1	Family

Pfam: PF00999

Catalyzed reactions (Rhea), 2 shown:

• Na(+)(in) + H(+)(out) = Na(+)(out) + H(+)(in) (RHEA:29419)
• K(+)(in) + H(+)(out) = K(+)(out) + H(+)(in) (RHEA:29467)

UniProt features (33 total): transmembrane region 12, sequence variant 9, sequence conflict 7, splice variant 2, chain 1, glycosylation site 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92581-F1	70.61	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 475

Glycosylation sites (1): 128

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-425986	Sodium/Proton exchangers
R-HSA-5619092	Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 407 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, ACTACCT_MIR196A_MIR196B, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_NEURON_PROJECTION_EXTENSION, KAAB_FAILED_HEART_ATRIUM_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_GROWTH, GTTAAAG_MIR302B, GOBP_NEUROGENESIS, CTATGCA_MIR153, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, YANG_BREAST_CANCER_ESR1_DN

GO Biological Process (19): monoatomic ion transport (GO:0006811), establishment of cell polarity (GO:0030010), axon extension (GO:0048675), neuron projection morphogenesis (GO:0048812), regulation of intracellular pH (GO:0051453), potassium ion transmembrane transport (GO:0071805), dendrite extension (GO:0097484), sodium ion import across plasma membrane (GO:0098719), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), regulation of pH (GO:0006885), brain-derived neurotrophic factor receptor signaling pathway (GO:0031547), sodium ion transmembrane transport (GO:0035725), synapse organization (GO:0050808), regulation of neurotrophin TRK receptor signaling pathway (GO:0051386), transmembrane transport (GO:0055085), dendritic spine development (GO:0060996), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), proton transmembrane transport (GO:1902600)

GO Molecular Function (5): sodium:proton antiporter activity (GO:0015385), potassium:proton antiporter activity (GO:0015386), identical protein binding (GO:0042802), protein binding (GO:0005515), antiporter activity (GO:0015297)

GO Cellular Component (18): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), endosome membrane (GO:0010008), membrane (GO:0016020), dendrite (GO:0030425), cytoplasmic vesicle (GO:0031410), axon terminus (GO:0043679), axonal spine (GO:0044308), synapse (GO:0045202), Schaffer collateral - CA1 synapse (GO:0098685), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metal ion SLC transporters	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	4
monoatomic cation transmembrane transport	3
endosome membrane	3
transport	2
neuron projection extension	2
regulation of biological quality	2
metal cation:proton antiporter activity	2
synapse	2
establishment or maintenance of cell polarity	1
axonogenesis	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
potassium ion transport	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
monoatomic ion transport	1
metal ion transport	1
monoatomic cation homeostasis	1
biological regulation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
sodium ion transport	1
cell junction organization	1
regulation of signal transduction	1
neurotrophin TRK receptor signaling pathway	1
regulation of cellular response to growth factor stimulus	1
cellular process	1
dendrite development	1
anatomical structure development	1
sodium ion transmembrane transporter activity	1
solute:potassium antiporter activity	1
protein binding	1
binding	1
secondary active transmembrane transporter activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1672 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC9A6	SLC9B2	Q86UD5	917
SLC9A6	DIPK2A	Q8NDZ4	826
SLC9A6	RACK1	P25388	733
SLC9A6	NPAS4	Q8IUM7	701
SLC9A6	SLC9B1	Q4ZJI4	599
SLC9A6	SLC9C1	Q4G0N8	598
SLC9A6	CDKL5	O76039	543
SLC9A6	MAPT	P10636	534
SLC9A6	SLC9C2	Q5TAH2	506
SLC9A6	PCDH19	Q8TAB3	505
SLC9A6	AGTR2	P50052	495
SLC9A6	UBE3A	P78355	485
SLC9A6	NHERF1	O14745	454
SLC9A6	HS3ST5	Q8IZT8	449
SLC9A6	PCDH10	Q9P2E7	447

IntAct

37 interactions, top by confidence:

A	B	Type	Score
RELL2	OXSR1	psi-mi:“MI:0914”(association)	0.830
SLC9A6	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
SLC1A5	GPR89A	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
SLC9A6	ALDH3A2	psi-mi:“MI:0914”(association)	0.530
SLC9A6	IFNGR1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
LGALS9	PODXL	psi-mi:“MI:0914”(association)	0.350
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.350
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC39A8	VAPB	psi-mi:“MI:0914”(association)	0.350
FNDC4	MT-ND2	psi-mi:“MI:0914”(association)	0.350
MBLAC2	STAT3	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
KIR2DL4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC39A8	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SLC31A2	PLSCR1	psi-mi:“MI:0914”(association)	0.350
LGALS9B	ABCC4	psi-mi:“MI:0914”(association)	0.350

BioGRID (158): SLC9A6 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), SLC9A7 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), FUT8 (Affinity Capture-MS), TBC1D32 (Affinity Capture-MS), CDK20 (Affinity Capture-MS), RAC3 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), DNAJC30 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), COA1 (Affinity Capture-MS), POMGNT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K2BF92, A0A6P3HVI0, A1L3P4, A2VDL4, A4IHB9, B9H7I1, D3ZJ25, D4A7H1, E7EXX2, F7B113, O00341, O35874, O54902, O57321, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P46411, P48763, P49281, P49282, P50482, P51906, P51907, P51912, P56564, Q0D7E4, Q3ZAS0, Q4R7S2, Q4ZJI4, Q5BKR2, Q5M7K3, Q5R6B8, Q6DFC0, Q86UD5, Q8BLV3

Diamond homologs: A1L3P4, B2RXE2, D3ZJ86, D4A7H1, F7B113, G3X939, M5A7P9, O13726, P19634, P23791, P26431, P26432, P26433, P26434, P48761, P48762, P48763, P48764, Q01345, Q04121, Q14940, Q28362, Q3ZAS0, Q4L208, Q4R8V4, Q552S0, Q56XP4, Q58916, Q5ZJ75, Q61165, Q68KI4, Q6AI14, Q84WG1, Q8BLV3, Q8BUE1, Q8BZ00, Q8IVB4, Q8R4D1, Q8RWU6, Q8S396

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SLC9A6	“down-regulates quantity”	hydron	relocalization
SLC9A6	“up-regulates quantity”	sodium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

716 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	25
Uncertain significance	225
Likely benign	196
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074430	NC_000023.10:g.(?135104735)(135106652_?)del	Pathogenic
11476	NM_001379110.1(SLC9A6):c.704_709del (p.Glu235_Ser236del)	Pathogenic
11477	NM_001379110.1(SLC9A6):c.1342C>T (p.Arg448Ter)	Pathogenic
11478	NM_001379110.1(SLC9A6):c.447+3_447+4delinsCC	Pathogenic
11479	NM_001379110.1(SLC9A6):c.452_453del (p.His151fs)	Pathogenic
1323617	NM_001379110.1(SLC9A6):c.886-1C>A	Pathogenic
1446671	NM_001379110.1(SLC9A6):c.806dup (p.Lys270fs)	Pathogenic
1448076	NM_001379110.1(SLC9A6):c.1644del (p.Trp548fs)	Pathogenic
159931	NM_001379110.1(SLC9A6):c.27del (p.Lys9fs)	Pathogenic
159932	NM_001379110.1(SLC9A6):c.2012T>G (p.Leu671Ter)	Pathogenic
167702	NM_001379110.1(SLC9A6):c.448-1G>A	Pathogenic
207248	NM_001379110.1(SLC9A6):c.370-9_370-5del	Pathogenic
207249	NM_006359.2(SLC9A6):c.585dupG	Pathogenic
207251	NM_001379110.1(SLC9A6):c.190dup (p.Leu64fs)	Pathogenic
207255	NM_001379110.1(SLC9A6):c.797_798del (p.Thr266fs)	Pathogenic
2126482	NM_001379110.1(SLC9A6):c.953G>A (p.Trp318Ter)	Pathogenic
2425582	NC_000023.10:g.(?135104725)(135106662_?)del	Pathogenic
2425584	NC_000023.10:g.(?135104725)(135104876_?)del	Pathogenic
246605	NM_001042537:c.916delC	Pathogenic
253442	GRCh37/hg19 Xq26.3(chrX:135067386-135068117)x0	Pathogenic
2579526	NM_001379110.1(SLC9A6):c.1570C>T (p.Gln524Ter)	Pathogenic
2707134	NM_001379110.1(SLC9A6):c.980G>A (p.Trp327Ter)	Pathogenic
2814239	NM_001379110.1(SLC9A6):c.445del (p.Arg149fs)	Pathogenic
2846648	NM_001379110.1(SLC9A6):c.1684dup (p.His562fs)	Pathogenic
29949	NM_001379110.1(SLC9A6):c.856_864del (p.Gly286_Ala288del)	Pathogenic
3245211	NC_000023.10:g.(?135067662)(135126883_?)del	Pathogenic
3245220	NC_000023.10:g.(?135112271)(135112341_?)del	Pathogenic
3655414	NM_001379110.1(SLC9A6):c.1186G>T (p.Gly396Ter)	Pathogenic
3655622	NM_001379110.1(SLC9A6):c.1418_1419del (p.Phe473fs)	Pathogenic
375585	NM_001379110.1(SLC9A6):c.726del (p.Ala243fs)	Pathogenic

SpliceAI

2881 predictions. Top by Δscore:

Variant	Effect	Δscore
X:135994780:TTCCA:T	acceptor_loss	1.0000
X:135994781:TCCA:T	acceptor_loss	1.0000
X:135994782:CCAGG:C	acceptor_loss	1.0000
X:135994783:CAG:C	acceptor_loss	1.0000
X:135994784:A:AG	acceptor_gain	1.0000
X:135994785:G:GG	acceptor_gain	1.0000
X:135998102:TAACA:T	acceptor_loss	1.0000
X:135998104:ACAG:A	acceptor_loss	1.0000
X:135998105:CAG:C	acceptor_loss	1.0000
X:135998106:A:AG	acceptor_gain	1.0000
X:135998107:G:GG	acceptor_gain	1.0000
X:135998183:AGGG:A	donor_loss	1.0000
X:135998184:GG:G	donor_gain	1.0000
X:135998185:GG:G	donor_gain	1.0000
X:135998186:G:GC	donor_loss	1.0000
X:135998186:G:GG	donor_gain	1.0000
X:135998187:T:G	donor_loss	1.0000
X:135998480:A:AG	acceptor_gain	1.0000
X:135998481:G:GG	acceptor_gain	1.0000
X:135998481:GA:G	acceptor_gain	1.0000
X:135998481:GAGAC:G	acceptor_gain	1.0000
X:135998557:GG:G	donor_gain	1.0000
X:135998558:GG:G	donor_gain	1.0000
X:135998965:CCAG:C	donor_loss	1.0000
X:135998968:GGT:G	donor_loss	1.0000
X:135998969:G:GA	donor_loss	1.0000
X:135998970:T:A	donor_loss	1.0000
X:136002106:A:AG	acceptor_gain	1.0000
X:136002107:G:GA	acceptor_gain	1.0000
X:136002107:GT:G	acceptor_gain	1.0000

AlphaMissense

4475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:135985827:G:C	G109R	1.000
X:135998157:T:A	I160K	1.000
X:135998168:G:C	G164R	1.000
X:135998169:G:A	G164D	1.000
X:135998963:A:G	D231G	1.000
X:136002171:G:A	G254D	1.000
X:136002176:A:C	S256R	1.000
X:136002178:T:A	S256R	1.000
X:136002178:T:G	S256R	1.000
X:136010554:G:C	G306R	1.000
X:136010555:G:A	G306D	1.000
X:136010566:G:A	G310R	1.000
X:136010566:G:C	G310R	1.000
X:136010567:G:A	G310E	1.000
X:136013372:G:C	G359R	1.000
X:136013373:G:A	G359D	1.000
X:136013384:G:C	A363P	1.000
X:136013404:T:A	N369K	1.000
X:136013404:T:G	N369K	1.000
X:136016684:T:C	F394L	1.000
X:136016686:C:A	F394L	1.000
X:136016686:C:G	F394L	1.000
X:136016696:G:A	G398R	1.000
X:136016696:G:C	G398R	1.000
X:136016697:G:A	G398E	1.000
X:136024338:G:C	G459R	1.000
X:135985827:G:T	G109C	0.999
X:135994786:G:A	G109D	0.999
X:135994786:G:T	G109V	0.999
X:135994797:G:C	G113R	0.999

dbSNP variants (sampled 300 via entrez): RS1000007098 (X:135981644 A>G), RS1000032334 (X:135986077 C>A,T), RS1000041062 (X:136046986 T>C), RS1000143069 (X:136035849 G>A), RS1000233422 (X:135991408 C>T), RS1000355572 (X:136000266 A>C), RS1000367102 (X:136000752 C>T), RS1000583848 (X:135990871 T>C), RS1000644697 (X:136009890 T>C), RS1000720382 (X:136019158 A>G), RS1000773158 (X:136019651 T>A), RS1000954718 (X:136009093 C>T), RS1001011558 (X:135984140 G>A,T), RS1001114875 (X:135972869 C>T), RS1001117169 (X:136037997 C>T)

Disease associations

OMIM: gene MIM:300231 | disease phenotypes: MIM:300243, MIM:301142, MIM:603047, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
Christianson syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Christianson syndrome	Definitive	XL

Mondo (11): Christianson syndrome (MONDO:0010278), intellectual disability (MONDO:0001071), neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment (MONDO:0976236), scoliosis (MONDO:0005392), amblyopia (MONDO:0001020), microcephaly (MONDO:0001149), strabismus (MONDO:0003432), hyperopia (MONDO:0004891), allergic disease (MONDO:0005271), astigmatism (MONDO:0011284), leukodystrophy (MONDO:0019046)

Orphanet (3): Christianson syndrome (Orphanet:85278), Leukodystrophy (Orphanet:68356), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000511	Vertical supranuclear gaze palsy
HP:0000574	Thick eyebrow
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000733	Motor stereotypy
HP:0000748	Inappropriate laughter
HP:0000751	Personality changes
HP:0000765	Abnormal thorax morphology
HP:0000767	Pectus excavatum
HP:0000774	Narrow chest
HP:0000939	Osteoporosis
HP:0001181	Adducted thumb
HP:0001238	Slender finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance

GWAS associations

0 associations (top):

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000550	Amblyopia	C10.228.140.055; C10.597.751.941.073; C11.966.073; C23.888.592.763.941.073
D001251	Astigmatism	C11.744.212
D006956	Hyperopia	C11.744.479
D006967	Hypersensitivity	C20.543
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D012600	Scoliosis	C05.116.900.800.875
D013285	Strabismus	C10.292.562.887; C11.590.810
C567484	Mental Retardation, X-Linked, Syndromic, Christianson Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC9 family of sodium/hydrogen exchangers

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	increases abundance, increases expression, decreases expression, affects cotreatment	2
Ozone	affects cotreatment, increases expression, increases abundance	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
3-iodothyronamine	affects uptake	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Ketamine	decreases expression	1
Lead	affects expression	1
Quercetin	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0KL	EMe-NH6W523XS7	Induced pluripotent stem cell	Male
CVCL_A0KM	EMe-NH6W523K5	Induced pluripotent stem cell	Male
CVCL_A0KN	EMe-NH6W523K17	Induced pluripotent stem cell	Male
CVCL_D4QU	HCT116-SLC9A6-KO-c16	Cancer cell line	Male
CVCL_D4QV	HCT116-SLC9A6-KO-c21	Cancer cell line	Male
CVCL_E0P6	Ubigene HeLa SLC9A6 KO	Cancer cell line	Female
CVCL_TP24	HAP1 SLC9A6 (-) 1	Cancer cell line	Male
CVCL_TP25	HAP1 SLC9A6 (-) 2	Cancer cell line	Male
CVCL_TP26	HAP1 SLC9A6 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders