SLC33A1

Summary

SLC33A1 (solute carrier family 33 member 1, HGNC:95) is a protein-coding gene on chromosome 3q25.31, encoding Acetyl-coenzyme A transporter 1 (O00400). Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based protein substrates, such as BACE1. It is a selective cancer dependency (DepMap: 12.8% of cell lines).

The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 9197 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Huppke-Brendel syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 295 total — 10 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.8% of screened cell lines
• MANE Select transcript: NM_004733

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:95
Approved symbol	SLC33A1
Name	solute carrier family 33 member 1
Location	3q25.31
Locus type	gene with protein product
Status	Approved
Aliases	AT-1, AT1
Ensembl gene	ENSG00000169359
Ensembl biotype	protein_coding
OMIM	603690
Entrez	9197

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000359479, ENST00000460729, ENST00000468581, ENST00000475842, ENST00000496772, ENST00000642438, ENST00000643144, ENST00000644094, ENST00000644855, ENST00000646424, ENST00000879567, ENST00000879568, ENST00000961491, ENST00000961492

RefSeq mRNA: 3 — MANE Select: NM_004733 NM_001190992, NM_001363883, NM_004733

CCDS: CCDS3173, CCDS87159

Canonical transcript exons

ENST00000643144 — 6 exons

Exon	Start	End
ENSE00001182133	155842432	155842619
ENSE00001870477	155821024	155828377
ENSE00003581899	155829688	155829903
ENSE00003611434	155833468	155833585
ENSE00003627699	155833857	155834041
ENSE00003818312	155853223	155854427

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 94.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.9502 / max 251.9940, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45243	33.5475	1822
45244	2.4028	1410

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	94.20	gold quality
body of pancreas	UBERON:0001150	93.94	gold quality
islet of Langerhans	UBERON:0000006	92.58	gold quality
pancreas	UBERON:0001264	92.49	gold quality
choroid plexus epithelium	UBERON:0003911	92.23	gold quality
cervix squamous epithelium	UBERON:0006922	92.19	silver quality
sperm	CL:0000019	92.14	silver quality
endothelial cell	CL:0000115	91.67	gold quality
seminal vesicle	UBERON:0000998	91.63	gold quality
stromal cell of endometrium	CL:0002255	91.07	gold quality
tendon of biceps brachii	UBERON:0008188	90.66	silver quality
nephron tubule	UBERON:0001231	90.03	gold quality
caput epididymis	UBERON:0004358	89.83	gold quality
endometrium	UBERON:0001295	89.61	gold quality
parietal pleura	UBERON:0002400	89.28	gold quality
gingival epithelium	UBERON:0001949	89.01	gold quality
calcaneal tendon	UBERON:0003701	88.71	gold quality
squamous epithelium	UBERON:0006914	88.69	gold quality
adrenal tissue	UBERON:0018303	88.57	gold quality
male germ cell	CL:0000015	88.51	silver quality
tendon	UBERON:0000043	88.46	gold quality
secondary oocyte	CL:0000655	88.22	gold quality
pleura	UBERON:0000977	88.21	gold quality
liver	UBERON:0002107	88.18	gold quality
right lobe of liver	UBERON:0001114	87.95	gold quality
esophagus squamous epithelium	UBERON:0006920	87.95	gold quality
jejunal mucosa	UBERON:0000399	87.79	gold quality
oviduct epithelium	UBERON:0004804	87.55	gold quality
visceral pleura	UBERON:0002401	87.44	gold quality
cauda epididymis	UBERON:0004360	87.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.85
E-MTAB-6142	no	93.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting SLC33A1, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• A missense mutation in SLC33A1 causes autosomal-dominant spastic paraplegia. (PMID:19061983)
• translocates acetyl-CoA into the ER lumen and is essential for cell viability (PMID:20826464)
• Homozygosity mapping displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1. (PMID:22243965)
• IRE1/XBP1 controls the induction of autophagy/ERAD(II) during the unfolded protein response by activating the ER membrane transporter SLC33A1/AT-1 (PMID:22787145)
• SLC33A1 can negatively regulate BMP signaling. (PMID:25402622)
• results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways. (PMID:27242167)
• Acetyl-CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway. (PMID:33479349)
• Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. (PMID:34414377)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc33a1	ENSDARG00000020085
mus_musculus	Slc33a1	ENSMUSG00000027822
rattus_norvegicus	Slc33a1	ENSRNOG00000010023
drosophila_melanogaster	CG9706	FBGN0036662
caenorhabditis_elegans		WBGENE00012033

Paralogs (1): MFSD3 (ENSG00000167700)

Protein

Protein identifiers

Acetyl-coenzyme A transporter 1 — O00400 (reviewed: O00400)

Alternative names: Solute carrier family 33 member 1

All UniProt accessions (8): A0A2R8Y359, A0A2R8Y5I5, A0A2R8YEX5, A0A2R8YF57, O00400, H7C532, H7C562, H7C577

UniProt curated annotations — full annotation on UniProt →

Function. Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based protein substrates, such as BACE1. Necessary for O-acetylation of gangliosides.

Subunit / interactions. Homodimerizes.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. With strongest signals in pancreas.

Disease relevance. Spastic paraplegia 42, autosomal dominant (SPG42) [MIM:612539] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry. Huppke-Brendel syndrome (HPBDS) [MIM:614482] An autosomal recessive disorder characterized by congenital cataracts, severe psychomotor retardation, and hearing loss associated with decreased serum ceruloplasmin and copper. Brain MRI shows cerebral and cerebellar atrophy and hypomyelination. The disease is caused by variants affecting the gene represented in this entry.

Induction. Expression is induced in presence of ceramide.

Similarity. Belongs to the SLC33A transporter family.

RefSeq proteins (3): NP_001177921, NP_001350812, NP_004724* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004752	AmpG_permease/AT-1	Family
IPR024371	AcetylCoA_trans_1-like	Family
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF13000

Catalyzed reactions (Rhea), 1 shown:

• acetyl-CoA(in) = acetyl-CoA(out) (RHEA:75039)

UniProt features (34 total): topological domain 12, transmembrane region 11, sequence variant 4, compositionally biased region 2, modified residue 2, chain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9MUN	ELECTRON MICROSCOPY	3.26
9M0S	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00400-F1	82.84	0.58

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 (2): 22, 42

Glycosylation sites (1): 103

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-425397	Transport of vitamins, nucleosides, and related molecules
R-HSA-5619061	Defective SLC33A1 causes spastic paraplegia 42 (SPG42)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 0 (showing top):

GO Biological Process (2): acetyl-CoA transmembrane transport (GO:0035348), transmembrane transport (GO:0055085)

GO Molecular Function (3): acetyl-CoA transmembrane transporter activity (GO:0008521), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (5): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC-mediated transmembrane transport	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
acetyl-CoA transport	2
purine-containing compound transmembrane transport	1
transport	1
cellular process	1
organophosphate ester transmembrane transporter activity	1
nucleobase-containing compound transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
identical protein binding	1
protein dimerization activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC33A1	NIPA1	Q7RTP0	617
SLC33A1	AP5Z1	O43299	574
SLC33A1	VPS37A	Q8NEZ2	566
SLC33A1	PNPLA6	Q8IY17	554
SLC33A1	WASHC5	Q12768	550
SLC33A1	NAT8	Q9UHE5	543
SLC33A1	ZFYVE26	Q68DK2	536
SLC33A1	REEP1	Q9H902	532
SLC33A1	SPAST	Q9UBP0	526
SLC33A1	SPG21	Q9NZD8	520
SLC33A1	GBA2	Q9HCG7	520
SLC33A1	AP4S1	Q9Y587	514
SLC33A1	SLC35A5	Q9BS91	507
SLC33A1	AP4B1	Q9Y6B7	506
SLC33A1	TECPR2	O15040	491

IntAct

58 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
TRAPPC1	TRAPPC13	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
CFTR	SLC33A1	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SLC33A1	RBM42	psi-mi:“MI:0915”(physical association)	0.400
SLC33A1	UBE2O	psi-mi:“MI:0915”(physical association)	0.400
SLC33A1	METTL8	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
rep	GPR89A	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
OPRL1	METTL15	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
AQP3	RTL8C	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350

BioGRID (282): SLC33A1 (Proximity Label-MS), SLC33A1 (Proximity Label-MS), SLC33A1 (Proximity Label-MS), SLC33A1 (Proximity Label-MS), SLC33A1 (Proximity Label-MS), ATP2A2 (Affinity Capture-MS), ATP5A1 (Affinity Capture-MS), ATP5E (Affinity Capture-MS), ATP5O (Affinity Capture-MS), CANX (Affinity Capture-MS), CLCN7 (Affinity Capture-MS), CLIC1 (Affinity Capture-MS), EEF1D (Affinity Capture-MS), EEF1G (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4ILB2, A0A8M9Q308, A1A4N1, A2CER7, A5D7V7, A8WGF7, B0S5Y3, B2RXV4, B5X4H8, O00400, O00476, O01735, O23596, P30638, P36836, P46029, P60815, Q11073, Q16348, Q28722, Q28FF3, Q503P5, Q5F4B8, Q5RBM3, Q5XGK0, Q63424, Q6AYY8, Q6DDL7, Q6DIT7, Q6GMG6, Q6PB15, Q7Z3Q1, Q84XI3, Q86WB7, Q91X85, Q944P0, Q99808, Q99J27, Q9BZD2, Q9C8X2

Diamond homologs: O00400, P24326, P38317, P38318, Q4V8E5, Q5U419, Q6AYY8, Q96ES6, Q99J27, Q9USW4, P0AE16, P0AE17, Q1RI01, Q4ULW4, Q92I85, Q9ZCG7, Q1RKF6, Q4UK37, Q68VW8, Q92GA9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Class A/1 (Rhodopsin-like receptors)	5	10.0×	6e-04
G alpha (i) signalling events	5	5.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	24.3×	5e-04
adenylate cyclase-activating G protein-coupled receptor signaling pathway	5	12.6×	5e-03
G protein-coupled receptor signaling pathway	9	7.2×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	1
Uncertain significance	158
Likely benign	80
Benign	16

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1070059	NM_004733.4(SLC33A1):c.1131C>G (p.Tyr377Ter)	Pathogenic
2425210	NC_000003.11:g.(?155560201)(155560428_?)del	Pathogenic
30375	NM_004733.4(SLC33A1):c.328G>C (p.Ala110Pro)	Pathogenic
30378	NM_004733.4(SLC33A1):c.614dup (p.Leu205fs)	Pathogenic
3725172	NM_004733.4(SLC33A1):c.992del (p.Thr331fs)	Pathogenic
6132	NM_004733.4(SLC33A1):c.339T>G (p.Ser113Arg)	Pathogenic
684757	NM_004733.4(SLC33A1):c.542_543del (p.Val181fs)	Pathogenic
684758	NM_004733.4(SLC33A1):c.1098C>G (p.Tyr366Ter)	Pathogenic
684759	NM_004733.4(SLC33A1):c.1267-1G>A	Pathogenic
684760	NM_004733.4(SLC33A1):c.1474_1482+9del	Pathogenic
812763	NM_004733.4(SLC33A1):c.963+1G>A	Likely pathogenic

SpliceAI

1490 predictions. Top by Δscore:

Variant	Effect	Δscore
3:155829684:TTA:T	donor_loss	1.0000
3:155829685:TAC:T	donor_loss	1.0000
3:155829686:A:AC	donor_gain	1.0000
3:155829686:A:AT	donor_loss	1.0000
3:155829686:AC:A	donor_gain	1.0000
3:155829687:C:CG	donor_gain	1.0000
3:155829687:CC:C	donor_gain	1.0000
3:155829687:CCT:C	donor_gain	1.0000
3:155829902:ACC:A	acceptor_loss	1.0000
3:155829903:CCT:C	acceptor_loss	1.0000
3:155829904:C:CC	acceptor_gain	1.0000
3:155829905:T:C	acceptor_loss	1.0000
3:155833936:T:C	donor_gain	1.0000
3:155833989:C:CA	donor_gain	1.0000
3:155834038:CAAT:C	acceptor_gain	1.0000
3:155834040:ATC:A	acceptor_loss	1.0000
3:155834042:CTGCA:C	acceptor_loss	1.0000
3:155834043:T:G	acceptor_loss	1.0000
3:155842426:TCTTA:T	donor_loss	1.0000
3:155842427:CTTA:C	donor_loss	1.0000
3:155842428:TTA:T	donor_loss	1.0000
3:155842429:TA:T	donor_loss	1.0000
3:155842430:A:AG	donor_loss	1.0000
3:155842604:C:CT	acceptor_gain	1.0000
3:155842604:C:T	acceptor_gain	1.0000
3:155828177:ATTAC:A	donor_loss	0.9900
3:155828178:TTA:T	donor_loss	0.9900
3:155828179:TACC:T	donor_loss	0.9900
3:155828180:ACCTT:A	donor_loss	0.9900
3:155828373:CAAAG:C	acceptor_gain	0.9900

AlphaMissense

3554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:155829799:A:C	N457K	1.000
3:155829799:A:T	N457K	1.000
3:155829818:A:G	L451P	1.000
3:155853339:C:T	G220D	1.000
3:155853340:C:G	G220R	1.000
3:155853347:A:C	N217K	1.000
3:155853347:A:T	N217K	1.000
3:155853405:T:A	D198V	1.000
3:155853406:C:G	D198H	1.000
3:155853411:G:T	A196D	1.000
3:155853416:G:C	D194E	1.000
3:155853416:G:T	D194E	1.000
3:155853417:T:G	D194A	1.000
3:155853571:A:G	W143R	1.000
3:155853571:A:T	W143R	1.000
3:155853625:A:G	W125R	1.000
3:155853625:A:T	W125R	1.000
3:155828231:C:A	W543C	0.999
3:155828231:C:G	W543C	0.999
3:155828233:A:G	W543R	0.999
3:155828233:A:T	W543R	0.999
3:155829786:A:G	W462R	0.999
3:155829786:A:T	W462R	0.999
3:155829797:A:G	L458P	0.999
3:155829811:A:C	N453K	0.999
3:155829811:A:T	N453K	0.999
3:155829836:C:T	G445E	0.999
3:155829850:A:C	S440R	0.999
3:155829850:A:T	S440R	0.999
3:155829852:T:G	S440R	0.999

dbSNP variants (sampled 300 via entrez): RS1000013550 (3:155848324 T>C), RS1000071672 (3:155841532 T>C), RS1000164702 (3:155837541 A>G), RS1000255932 (3:155836850 C>T), RS1000589979 (3:155838314 A>C,G,T), RS1000632340 (3:155846091 C>T), RS1000639825 (3:155839544 C>T), RS1000725159 (3:155846390 G>C), RS1000739049 (3:155852199 A>T), RS1000740724 (3:155831692 T>C), RS1000757491 (3:155824039 T>C), RS1000807084 (3:155850877 A>G), RS1001123798 (3:155832560 G>A), RS1001194311 (3:155831969 C>T), RS1001439433 (3:155837696 T>A)

Disease associations

OMIM: gene MIM:603690 | disease phenotypes: MIM:612539, MIM:303350, MIM:614482

GenCC curated gene-disease

Disease	Classification	Inheritance
Huppke-Brendel syndrome	Definitive	Autosomal recessive
hereditary spastic paraplegia 42	Supportive	Autosomal dominant

Mondo (4): hereditary spastic paraplegia 42 (MONDO:0012928), hereditary spastic paraplegia (MONDO:0019064), Huppke-Brendel syndrome (MONDO:0013772), hypothyroidism (MONDO:0005420)

Orphanet (3): Autosomal dominant spastic paraplegia type 42 (Orphanet:171863), Hereditary spastic paraplegia (Orphanet:685), Congenital cataract-hearing loss-severe developmental delay syndrome (Orphanet:300313)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000519	Developmental cataract
HP:0000639	Nystagmus
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001272	Cerebellar atrophy
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002169	Clonus
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002395	Lower limb hyperreflexia
HP:0002540	Inability to walk
HP:0002921	Abnormal cerebrospinal fluid morphology
HP:0003202	Skeletal muscle atrophy
HP:0003429	CNS hypomyelination
HP:0003457	EMG abnormality
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0003819	Death in childhood
HP:0006895	Lower limb hypertonia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006613_137	Triglycerides	2.000000e-09
GCST007350_1	Focal epilepsy (with hippocampal sclerosis)	1.000000e-11
GCST90011898_153	Alanine aminotransferase levels	8.000000e-09
GCST90011900_82	Serum alkaline phosphatase levels	2.000000e-10
GCST90013405_55	Liver enzyme levels (alanine transaminase)	7.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007037	Hypothyroidism	C19.874.482
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C567262	Spastic Paraplegia 42, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3638338 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC33 acetylCoA transporter

Binding affinities (BindingDB)

145 measured of 145 human assays (145 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US8592431, 167	IC50	0.8 nM	US-8592431: Fused ring compound and use thereof
US8592431, 135	IC50	0.9 nM	US-8592431: Fused ring compound and use thereof
US8592431, 147	IC50	1 nM	US-8592431: Fused ring compound and use thereof
US8592431, 264	IC50	1 nM	US-8592431: Fused ring compound and use thereof
US8592431, 242	IC50	1.2 nM	US-8592431: Fused ring compound and use thereof
US8592431, 354	IC50	1.2 nM	US-8592431: Fused ring compound and use thereof
US8592431, 376	IC50	1.2 nM	US-8592431: Fused ring compound and use thereof
US8592431, 2	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 117	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 134	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 136	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 138	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 166	IC50	1.3 nM	US-8592431: Fused ring compound and use thereof
US8592431, 69	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 137	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 144	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 150	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 168	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 169	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 339	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 352	IC50	1.4 nM	US-8592431: Fused ring compound and use thereof
US8592431, 73	IC50	1.5 nM	US-8592431: Fused ring compound and use thereof
US8592431, 83	IC50	1.5 nM	US-8592431: Fused ring compound and use thereof
US8592431, 108	IC50	1.5 nM	US-8592431: Fused ring compound and use thereof
US8592431, 113	IC50	1.5 nM	US-8592431: Fused ring compound and use thereof
US8592431, 228	IC50	1.5 nM	US-8592431: Fused ring compound and use thereof
US8592431, 151	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 163	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 170	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 191	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 216	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 338	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 413	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 437	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 521	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 155	IC50	1.6 nM	US-8592431: Fused ring compound and use thereof
US8592431, 5	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 68	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 139	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 173	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 273	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 296	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 355	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 360	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 435	IC50	1.7 nM	US-8592431: Fused ring compound and use thereof
US8592431, 10	IC50	1.8 nM	US-8592431: Fused ring compound and use thereof
US8592431, 78	IC50	1.8 nM	US-8592431: Fused ring compound and use thereof
US8592431, 281	IC50	1.8 nM	US-8592431: Fused ring compound and use thereof
US8592431, 299	IC50	1.8 nM	US-8592431: Fused ring compound and use thereof
US8592431, 400	IC50	1.8 nM	US-8592431: Fused ring compound and use thereof

ChEMBL bioactivities

153 potent at pChembl≥5 of 153 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.10	IC50	0.8	nM	CHEMBL3648555
9.05	IC50	0.9	nM	CHEMBL3648538
9.00	IC50	1	nM	CHEMBL3648544
9.00	IC50	1	nM	CHEMBL3648553
8.92	IC50	1.2	nM	CHEMBL3648551
8.92	IC50	1.2	nM	CHEMBL3639474
8.92	IC50	1.2	nM	CHEMBL3648629
8.89	IC50	1.3	nM	CHEMBL3648511
8.89	IC50	1.3	nM	CHEMBL3648532
8.89	IC50	1.3	nM	CHEMBL3648537
8.89	IC50	1.3	nM	CHEMBL3648539
8.89	IC50	1.3	nM	CHEMBL3648541
8.89	IC50	1.3	nM	CHEMBL3648551
8.89	IC50	1.3	nM	CHEMBL3648554
8.85	IC50	1.4	nM	CHEMBL3648522
8.85	IC50	1.4	nM	CHEMBL3648540
8.85	IC50	1.4	nM	CHEMBL3648543
8.85	IC50	1.4	nM	CHEMBL3648546
8.85	IC50	1.4	nM	CHEMBL3648556
8.85	IC50	1.4	nM	CHEMBL3648557
8.85	IC50	1.4	nM	CHEMBL3648616
8.85	IC50	1.4	nM	CHEMBL3648619
8.82	IC50	1.5	nM	CHEMBL3648523
8.82	IC50	1.5	nM	CHEMBL3648526
8.82	IC50	1.5	nM	CHEMBL3648528
8.82	IC50	1.5	nM	CHEMBL3648530
8.82	IC50	1.5	nM	CHEMBL3648581
8.80	IC50	1.6	nM	CHEMBL3651826
8.80	IC50	1.6	nM	CHEMBL3648547
8.80	IC50	1.6	nM	CHEMBL3648552
8.80	IC50	1.6	nM	CHEMBL3648558
8.80	IC50	1.6	nM	CHEMBL3648569
8.80	IC50	1.6	nM	CHEMBL3648578
8.80	IC50	1.6	nM	CHEMBL3648615
8.80	IC50	1.6	nM	CHEMBL3648638
8.80	IC50	1.6	nM	CHEMBL3892965
8.80	IC50	1.6	nM	CHEMBL3937585
8.77	IC50	1.7	nM	CHEMBL3648513
8.77	IC50	1.7	nM	CHEMBL3648521
8.77	IC50	1.7	nM	CHEMBL3648542
8.77	IC50	1.7	nM	CHEMBL3648559
8.77	IC50	1.7	nM	CHEMBL3648591
8.77	IC50	1.7	nM	CHEMBL3648606
8.77	IC50	1.7	nM	CHEMBL3648620
8.77	IC50	1.7	nM	CHEMBL3648621
8.77	IC50	1.7	nM	CHEMBL3930046
8.74	IC50	1.8	nM	CHEMBL3648516
8.74	IC50	1.8	nM	CHEMBL3648525
8.74	IC50	1.8	nM	CHEMBL3648597
8.74	IC50	1.8	nM	CHEMBL3648608

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149417: Binding affinity to human SLC33A1 incubated for 45 mins by Kinobead based pull down assay	kd	1.5205	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
periodate-oxidized adenosine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
abrine	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Benzo(a)pyrene	decreases expression	1
Copper	affects binding, increases expression	1
Drugs, Chinese Herbal	increases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705164	Binding	Binding Assay: The binding assay was performed using 22.5 pM [125I]-angiotensin II [manufactured by PerkinElmer, USA] (9 μg) in the presence of AT1 membrane and test compound.	Fused ring compound and use thereof

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4LR	HCT116-SLC33A1-KO-c6	Cancer cell line	Male
CVCL_D4LS	HCT116-SLC33A1-KO-c9	Cancer cell line	Male
CVCL_D9RZ	Ubigene HEK293 SLC33A1 KO	Transformed cell line	Female
CVCL_TM99	HAP1 SLC33A1 (-) 1	Cancer cell line	Male
CVCL_TN00	HAP1 SLC33A1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00001730	PHASE4	COMPLETED	Study of Radioiodine (131-I) Uptake Following Administration of Thyrogen and Hypothyroid States During Thyroid Hormone Withdrawal.
NCT00111735	PHASE4	UNKNOWN	Thyroxine Titration Study
NCT00206375	PHASE4	TERMINATED	Growth Hormone and GnRH Agonist in Adolescents With Acquired Hypothyroidism
NCT00565864	PHASE4	COMPLETED	Neurocognitive and Metabolic Effects of Mild Hypothyroidism
NCT01379170	PHASE4	UNKNOWN	Thyroid Study Type 2 Diabetes Mellitus (T2DM)
NCT01536678	PHASE4	COMPLETED	Bioequivalence of Two Levothyroxine Tablet Formulations in Healthy Indian Volunteers
NCT01647750	PHASE4	COMPLETED	Study of Optimal Replacement of Thyroxine in the Elderly
NCT01769157	PHASE4	COMPLETED	Effects of L-carnitine on Hypothyroidism
NCT01831869	PHASE4	UNKNOWN	Effect of L-Thyroxine on Lipid Profiles and Atherosclerosis in Subclinical Hypothyroidism
NCT01848171	PHASE4	UNKNOWN	Effects of L-thyroxine Replacement on Serum Lipid and Atherosclerosis in Hypothyroidism
NCT01921452	PHASE4	COMPLETED	Study to Verify Clinical Utility of Point-of-Care (POC) Thyroid Stimulating Hormone (TSH) Test Kits as Compared to Third Generation TSH Test Kit
NCT02280330	PHASE4	COMPLETED	Iodine Status of Preschoolers Given Micronutrient Powder for 6 Months
NCT02512978	PHASE4	UNKNOWN	Thyroid Hormone Replacement for Hypothyroidism and Acute Myocardial Infarction(ThyroHeart-AMI)
NCT02577367	PHASE4	WITHDRAWN	Mean Percentage of Levothyroxine Dosage Increase in Patients With Hypothyroidism Started on Enteral Feeding
NCT02917863	PHASE4	UNKNOWN	Randomized Crossover Trial for the Evaluation of the Possible Effects in the Intestine of Two Different Pharmaceutical Forms of L - Thyroxine in Patients With Primary Acquired Hypothyroidism
NCT03342001	PHASE4	COMPLETED	Hypothyroidism Treated With Calcitonin
NCT03631771	PHASE4	WITHDRAWN	Pediatric Risk of Hypothyroidism With Iodinated Contrast Media
NCT03779906	PHASE4	TERMINATED	Thyroid Function of Pediatric Subjects Following Isovue® Administration
NCT04747275	PHASE4	TERMINATED	Use of Liquid Stable Levothyroxine in Trisomy 21 Pediatric Patients
NCT04878614	PHASE4	TERMINATED	Comparison of Levothyroxine Formulation in Hypothyroid Patients With Enteral Feeding
NCT05247476	PHASE4	UNKNOWN	Type 2 Deiodinase Gene Polymorphism and the Treatment of Hypothyroidism Caused by Thyroidectomy in Thyroid Cancer Patients.
NCT06073665	PHASE4	RECRUITING	Dosing of LT4 in Older Individuals
NCT06096454	PHASE4	UNKNOWN	Effect of Life Style Modification and Metformin on Hypothyroidism With Insulin Resistance
NCT01204359	PHASE3	UNKNOWN	The Prospective Study of Standard Treatment of Graves Disease Iodine 131 and Prevention of Adverse Reactions
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT01800617	PHASE2	COMPLETED	A Study of T3 Therapy in Patients With Hypothyroidism
NCT01916304	PHASE2	COMPLETED	Study of Dose Adjustment From Levothyroxine to a New Levothyroxine Sodium Test Formulation
NCT03627611	PHASE2	COMPLETED	Identification of Non-responders to Levothyroxine Therapy
NCT04124705	PHASE2	COMPLETED	A Study of Armour® Thyroid Compared to Synthetic T4 (Levothyroxine) in Previously Hypothyroid Participants
NCT04782856	PHASE2	COMPLETED	Energy Metabolism in Thyroidectomized Patients
NCT05412979	PHASE2	COMPLETED	A Study Evaluating the Safety and Efficacy of Hormone Replacement Therapy With ST-1891 Compared to Levothyroxine in Patients With Primary Hypothyroidism
NCT05712421	PHASE2	COMPLETED	A Study Evaluation the Safety and Efficacy of Hormone Replacement Therapy With North Star Compared to Levothyroxine in Patients With Primary Hypothyroidism
NCT05733078	PHASE2	UNKNOWN	Effect of Vitamin C Supplementation in Patients With Primary Hypothyroidism
NCT05804149	PHASE2	COMPLETED	Effect of Acupuncture and Low Caloric Diet on Primary Hypothyroidism and Irregular Menstruation in Infertile Women
NCT05823012	PHASE2	COMPLETED	Study of XP-8121 For the Treatment of Adult Subjects With Hypothyroidism
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)