MFSD8

Summary

MFSD8 (major facilitator superfamily domain containing 8, HGNC:28486) is a protein-coding gene on chromosome 4q28.2, encoding Major facilitator superfamily domain-containing protein 8 (Q8NHS3). Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function.

This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL).

Source: NCBI Gene 256471 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,048 total — 92 pathogenic, 64 likely-pathogenic
• Phenotypes (HPO): 41
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001371596

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28486
Approved symbol	MFSD8
Name	major facilitator superfamily domain containing 8
Location	4q28.2
Locus type	gene with protein product
Status	Approved
Aliases	SLC74A1, MGC33302
Ensembl gene	ENSG00000164073
Ensembl biotype	protein_coding
OMIM	611124
Entrez	256471

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 26 protein_coding, 26 nonsense_mediated_decay, 7 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000296468, ENST00000503928, ENST00000504126, ENST00000505284, ENST00000508441, ENST00000509826, ENST00000513559, ENST00000515130, ENST00000641003, ENST00000641025, ENST00000641092, ENST00000641133, ENST00000641134, ENST00000641140, ENST00000641146, ENST00000641147, ENST00000641178, ENST00000641186, ENST00000641228, ENST00000641243, ENST00000641264, ENST00000641332, ENST00000641340, ENST00000641356, ENST00000641369, ENST00000641388, ENST00000641393, ENST00000641397, ENST00000641413, ENST00000641434, ENST00000641447, ENST00000641464, ENST00000641482, ENST00000641503, ENST00000641508, ENST00000641509, ENST00000641538, ENST00000641558, ENST00000641590, ENST00000641658, ENST00000641686, ENST00000641690, ENST00000641695, ENST00000641742, ENST00000641743, ENST00000641748, ENST00000641753, ENST00000641774, ENST00000641776, ENST00000641830, ENST00000641843, ENST00000641869, ENST00000641870, ENST00000641882, ENST00000641928, ENST00000641949, ENST00000642012, ENST00000642034, ENST00000642042, ENST00000642078, ENST00000642121, ENST00000642143, ENST00000938850, ENST00000945724

RefSeq mRNA: 12 — MANE Select: NM_001371596 NM_001363520, NM_001363521, NM_001371590, NM_001371591, NM_001371592, NM_001371593, NM_001371594, NM_001371595, NM_001371596, NM_001410765, NM_001410766, NM_152778

CCDS: CCDS3736, CCDS87255, CCDS87259, CCDS93622, CCDS93623, CCDS93626, CCDS93627, CCDS93628

Canonical transcript exons

ENST00000641686 — 12 exons

Exon	Start	End
ENSE00001081122	127921860	127921963
ENSE00003521365	127938783	127938838
ENSE00003578948	127921524	127921771
ENSE00003631626	127932985	127933093
ENSE00003642098	127942045	127942158
ENSE00003644201	127949804	127949847
ENSE00003657079	127939853	127939997
ENSE00003673029	127943752	127943992
ENSE00003677619	127957501	127957592
ENSE00003691083	127930683	127930817
ENSE00003813243	127917805	127920836
ENSE00003899542	127965072	127965173

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 91.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9889 / max 117.1167, expressed in 1768 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53894	8.7827	1730
53895	1.3696	910
53896	0.8367	426

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	91.04	gold quality
adrenal tissue	UBERON:0018303	89.39	gold quality
calcaneal tendon	UBERON:0003701	89.26	gold quality
body of pancreas	UBERON:0001150	88.65	gold quality
bone marrow cell	CL:0002092	88.02	gold quality
colonic epithelium	UBERON:0000397	87.81	gold quality
cerebellar hemisphere	UBERON:0002245	87.14	gold quality
cerebellar cortex	UBERON:0002129	86.98	gold quality
sural nerve	UBERON:0015488	86.74	gold quality
epithelial cell of pancreas	CL:0000083	86.71	gold quality
monocyte	CL:0000576	86.46	gold quality
pancreas	UBERON:0001264	86.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.41	gold quality
cerebellum	UBERON:0002037	86.32	gold quality
adenohypophysis	UBERON:0002196	86.25	gold quality
mucosa of stomach	UBERON:0001199	86.19	gold quality
skin of leg	UBERON:0001511	86.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.01	gold quality
leukocyte	CL:0000738	85.97	gold quality
ventricular zone	UBERON:0003053	85.81	gold quality
endothelial cell	CL:0000115	85.72	gold quality
skin of abdomen	UBERON:0001416	85.67	gold quality
pituitary gland	UBERON:0000007	85.53	gold quality
left ovary	UBERON:0002119	85.46	gold quality
right lobe of liver	UBERON:0001114	85.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.19	gold quality
minor salivary gland	UBERON:0001830	85.10	gold quality
skin of hip	UBERON:0001554	85.06	gold quality
spleen	UBERON:0002106	85.04	gold quality
upper leg skin	UBERON:0004262	84.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

173 targeting MFSD8, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
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-3617-3P	99.98	67.86	918
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• MFSD8 gene is involved in late-infantile-onset neuronal ceroid lipofuscinose;it was mapped to chromosome 4q28.1-q28.2. (PMID:17564970)
• Results describe a novel mutation in the MFSD8 gene, responsible for neuronal ceroid lipofuscinoses, in a consanguineous Egyptian family (PMID:18850119)
• Study contributes to a better molecular characterization of Italian NCL cases, and will facilitate medical genetic counseling in such families. (PMID:19177532)
• CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. (PMID:19201763)
• Data show that neuronal ceroid lipofuscinosis in a Saudi family is due to a homozygous novel mutation in the most recently described NCL gene (MFSD8). (PMID:19277732)
• Expression and lysosomal targeting of CLN7 are reported. (PMID:20826447)
• This study showed that Gene disruption of Mfsd8 provides animal model for CLN7 disease. (PMID:24423645)
• In this study, we identified variants in MFSD8 as a novel cause of nonsyndromic autosomal recessive macular dystrophy with central cone involvement. (PMID:25227500)
• A mutation in MFSD8, c.472G>A (p.Gly158Ser), segregates with the disease phenotype in variant late infantile neuronal ceroid lipofuscinosis. (PMID:25270050)
• MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation (PMID:25439737)
• This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. (PMID:28586915)
• Quantification revealed that the amounts of 12 different soluble lysosomal proteins were significantly reduced in Cln7 ko MEFs compared with wild-type controls. One of the most significantly depleted lysosomal proteins was Cln5 protein that underlies another distinct neuronal ceroid lipofuscinosis disorder (PMID:29514215)
• We identified a novel homozygous mutation in MFSD8 gene. (PMID:30144815)
• that MFSD8-associated lysosomal dysfunction may contribute to frontotemporal lobar degeneration pathology (PMID:30382371)
• Here and for the first time, we reported on two previously variant late-infantile neuronal ceroid lipofuscinoses-associated variants in MFSD8 but in association with a form of cone-rod dystrophy known as non-syndromic macular dystrophy with central cone involvement. (PMID:31006324)
• Mutation analysis of MFSD8 in an amyotrophic lateral sclerosis cohort from mainland China. (PMID:33226711)
• Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis. (PMID:35087090)
• A Novel, Apparently Silent Variant in MFSD8 Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability. (PMID:35216386)
• Contribution of Whole-Genome Sequencing and Transcript Analysis to Decipher Retinal Diseases Associated with MFSD8 Variants. (PMID:35457110)
• Maculopathy and adult-onset ataxia in patients with biallelic MFSD8 variants. (PMID:39108195)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	mfsd8	ENSDARG00000103235
mus_musculus	Mfsd8	ENSMUSG00000025759
rattus_norvegicus	Mfsd8	ENSRNOG00000012729
drosophila_melanogaster	Cln7	FBGN0035767
caenorhabditis_elegans		WBGENE00010182
caenorhabditis_elegans		WBGENE00010282
caenorhabditis_elegans		WBGENE00012222
caenorhabditis_elegans		WBGENE00016093
caenorhabditis_elegans		WBGENE00016094
caenorhabditis_elegans		WBGENE00016095
caenorhabditis_elegans		WBGENE00017861
caenorhabditis_elegans		WBGENE00021814
caenorhabditis_elegans		WBGENE00021870

Paralogs (6): MFSD10 (ENSG00000109736), MFSD1 (ENSG00000118855), MFSD9 (ENSG00000135953), MFSD14B (ENSG00000148110), MFSD14A (ENSG00000156875), MFSD5 (ENSG00000182544)

Protein

Protein identifiers

Major facilitator superfamily domain-containing protein 8 — Q8NHS3 (reviewed: Q8NHS3)

Alternative names: Ceroid-lipofuscinosis neuronal protein 7

All UniProt accessions (34): Q8NHS3, A0A286YER2, A0A286YEV4, A0A286YEV9, A0A286YEW2, A0A286YEW6, A0A286YEW7, A0A286YEW8, A0A286YEX1, A0A286YEY8, A0A286YF00, A0A286YF45, A0A286YF51, A0A286YF72, A0A286YF73, A0A286YF82, A0A286YF93, A0A286YFB5, A0A286YFC6, A0A286YFE6, A0A286YFE7, A0A286YFF1, A0A286YFF5, A0A286YFG7, A0A286YFH3, A0A286YFH9, A0A286YFI8, A0A286YFI9, A0A286YFJ5, A0A286YFK4, A0A286YFM2, A0A286YFM7, B7Z2B2, E7ERQ4

UniProt curated annotations — full annotation on UniProt →

Function. Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function. Conducts chloride currents up to hundreds of picoamperes. Regulates lysosomal calcium content by reducing the lysosomal membrane potential, thereby activating TRPML1 channel and further release of lysosomal calcium ions. Regulates the pH in endolysosomal compartments and may contribute to progressive acidification from endosome to lysosome. Permeable to other halides such as iodide and fluoride ions.

Subcellular location. Endosome membrane. Lysosome membrane.

Tissue specificity. Expressed at very low levels in all tissues tested.

Disease relevance. Ceroid lipofuscinosis, neuronal, 7 (CLN7) [MIM:610951] A form of neuronal ceroid lipofuscinosis with onset in early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment patterns observed most often in neuronal ceroid lipofuscinosis type 7 comprise mixed combinations of granular, curvilinear, fingerprint, and rectilinear profiles. The disease is caused by variants affecting the gene represented in this entry. Macular dystrophy with central cone involvement (CCMD) [MIM:616170] An ocular disease characterized by decreased visual acuity, slight pigmentary changes and color vision abnormalities, becoming apparent in the third to sixth decade of life. Fundus anomalies are variable and include bull’s eye maculopathy, severe atrophy of central fovea, relatively spared fovea with surrounding atrophic ring, central retinal pigment epithelium and/or choroid changes, pale or atrophic peripapillary area, pale optic disk, relatively spared periphery, and slightly or moderately attenuated vessels. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by chloride channel blockers 4,4’-diisothiocyano-2,2’-stilbenedisulfonate (DIDS), niflumic acid (NFA), and 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB).

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the major facilitator superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NHS3-1	1	yes
Q8NHS3-2	2

RefSeq proteins (12): NP_001350449, NP_001350450, NP_001358519, NP_001358520, NP_001358521, NP_001358522, NP_001358523, NP_001358524, NP_001358525, NP_001397694, NP_001397695, NP_689991 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR051068	MFS_Domain-Containing_Protein	Family

Pfam: PF07690

Catalyzed reactions (Rhea), 3 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• iodide(out) = iodide(in) (RHEA:66324)
• fluoride(in) = fluoride(out) (RHEA:76159)

UniProt features (59 total): sequence variant 19, topological domain 13, transmembrane region 12, splice variant 4, mutagenesis site 4, glycosylation site 2, sequence conflict 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHS3-F1	83.20	0.51

Functional residue map

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

Glycosylation sites (2): 371, 376

Mutagenesis-validated functional residues (4):

Position	Phenotype
13–14	mistargeted to the plasma membrane.
153	decreased chloride channel activity.
287	decreased chloride channel activity.
438	decreased chloride channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 287 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GCM_MAP4K4, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GCM_GSPT1, GOCC_VACUOLAR_MEMBRANE, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_INORGANIC_ANION_TRANSPORT

GO Biological Process (36): glycolytic process (GO:0006096), glycolipid metabolic process (GO:0006664), mitochondrion organization (GO:0007005), lysosome organization (GO:0007040), determination of adult lifespan (GO:0008340), glycoprotein metabolic process (GO:0009100), gene expression (GO:0010467), regulation of autophagy (GO:0010506), microglia differentiation (GO:0014004), multicellular organism growth (GO:0035264), TORC1 signaling (GO:0038202), negative regulation of neuron apoptotic process (GO:0043524), neuron development (GO:0048666), astrocyte differentiation (GO:0048708), protein stabilization (GO:0050821), neuromuscular process (GO:0050905), maintenance of location (GO:0051235), neuron apoptotic process (GO:0051402), retina development in camera-type eye (GO:0060041), motor behavior (GO:0061744), inclusion body assembly (GO:0070841), reactive oxygen species metabolic process (GO:0072593), autophagosome maturation (GO:0097352), lysosomal protein catabolic process (GO:1905146), regulation of lysosomal protein catabolic process (GO:1905165), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), autophagy (GO:0006914), apoptotic process (GO:0006915), iodide transport (GO:0015705), monoatomic ion transmembrane transport (GO:0034220), gliogenesis (GO:0042063), cellular respiration (GO:0045333), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476), fluoride transmembrane transport (GO:1903424)

GO Molecular Function (4): chloride channel activity (GO:0005254), iodide transmembrane transporter activity (GO:0015111), fluoride channel activity (GO:0062054), transmembrane transporter activity (GO:0022857)

GO Cellular Component (8): mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), endosome membrane (GO:0010008), chloride channel complex (GO:0034707), lysosome (GO:0005764), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
multicellular organismal process	2
central nervous system development	2
glial cell differentiation	2
monoatomic anion channel activity	2
cellular anatomical structure	2
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
liposaccharide metabolic process	1
organelle organization	1
lytic vacuole organization	1
protein metabolic process	1
carbohydrate derivative metabolic process	1
macromolecule biosynthetic process	1
autophagy	1
regulation of catabolic process	1
macrophage differentiation	1
developmental growth	1
TOR signaling	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
neuron differentiation	1
cell development	1
regulation of protein stability	1
nervous system process	1
localization	1
apoptotic process	1
camera-type eye development	1
anatomical structure development	1

Protein interactions and networks

STRING

1124 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MFSD8	CLN8	Q9UBY8	963
MFSD8	CLN3	Q13286	951
MFSD8	CLN6	Q9NWW5	948
MFSD8	CLN5	O75503	938
MFSD8	PPT1	P50897	915
MFSD8	DNAJC5	Q9H3Z4	838
MFSD8	CTSD	P07339	787
MFSD8	KCTD7	Q96MP8	770
MFSD8	CTSF	Q9UBX1	708
MFSD8	TPP1	O14773	686
MFSD8	ATP13A2	Q9NQ11	593
MFSD8	PPT2	Q9UMR5	558
MFSD8	MFSD6	Q6ZSS7	555
MFSD8	HGSNAT	Q68CP4	546
MFSD8	INTU	Q9ULD6	542

IntAct

75 interactions, top by confidence:

A	B	Type	Score
EPHX1	MFSD8	psi-mi:“MI:0914”(association)	0.640
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
ZACN	GPAA1	psi-mi:“MI:0914”(association)	0.530
ASGR2	MT-CO1	psi-mi:“MI:0914”(association)	0.530
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
S1PR2	PALM3	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
SLC22A16	APBA3	psi-mi:“MI:0914”(association)	0.530
MFSD8	FAM241A	psi-mi:“MI:0914”(association)	0.530
ADGRE5	TMEM223	psi-mi:“MI:0914”(association)	0.350
YIPF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
TNFSF8	NME4	psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.350
P2RY12	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (206): MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS), MFSD8 (Affinity Capture-MS)

ESM2 similar proteins: A1L272, A6QL92, B8AF63, E2RFJ3, E7EXX2, O35458, O35633, O54902, O80605, P49281, P49282, P51027, P57057, P58355, Q0VA82, Q28CV2, Q569T7, Q5F383, Q5R6J3, Q5RD30, Q5U3U7, Q62052, Q640L2, Q6DEJ6, Q6DIV6, Q6GPQ3, Q6GQE1, Q6P499, Q6PF45, Q6YK44, Q7RTT9, Q8BGN5, Q8BH31, Q8CBH5, Q8MIQ9, Q8NA29, Q8NBI5, Q8NHS3, Q8R070, Q8R139

Diamond homologs: P0A0J4, P0A0J5, P0A0J6, P0A0J7, Q0VA82, Q5HHX4, Q6GBD5, Q6GIU7, Q6GPQ3, Q8BH31, Q8NHS3, B0XZV4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
GPCR ligand binding	7	8.8×	1e-03
Class A/1 (Rhodopsin-like receptors)	6	8.7×	3e-03
G alpha (i) signalling events	11	8.4×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	8	23.3×	9e-07
calcium-mediated signaling	6	14.7×	4e-04
phospholipase C-activating G protein-coupled receptor signaling pathway	7	12.3×	3e-04
positive regulation of cytosolic calcium ion concentration	7	10.9×	4e-04
adenylate cyclase-activating G protein-coupled receptor signaling pathway	6	9.1×	3e-03
G protein-coupled receptor signaling pathway	14	6.8×	4e-06
immune response	9	5.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1048 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	64
Uncertain significance	380
Likely benign	390
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1002	NM_001371596.2(MFSD8):c.1286G>A (p.Gly429Asp)	Pathogenic
1003	NM_001371596.2(MFSD8):c.894T>G (p.Tyr298Ter)	Pathogenic
1007	NM_001371596.2(MFSD8):c.468_469delinsCC (p.Ala157Pro)	Pathogenic
1050805	NM_001371596.2(MFSD8):c.1437G>A (p.Trp479Ter)	Pathogenic
1069576	NC_000004.11:g.(?128886217)(128886288_?)del	Pathogenic
1069577	NC_000004.11:g.(?128841785)(128843128_?)del	Pathogenic
1073057	NM_001371596.2(MFSD8):c.878del (p.Pro292_Leu293insTer)	Pathogenic
1073549	NM_001371596.2(MFSD8):c.1113del (p.Asn371fs)	Pathogenic
1073899	NM_001371596.2(MFSD8):c.1120del (p.Ile374fs)	Pathogenic
1074190	NM_001371596.2(MFSD8):c.1316_1322del (p.Thr439fs)	Pathogenic
1074681	NM_001371596.2(MFSD8):c.1217_1218dup (p.Trp407fs)	Pathogenic
1075481	NM_001371596.2(MFSD8):c.136_137del (p.Met46fs)	Pathogenic
1206979	NM_001371596.2(MFSD8):c.259C>T (p.Gln87Ter)	Pathogenic
1252058	NM_001371596.2(MFSD8):c.1354_1369del (p.Gly451_Val452insTer)	Pathogenic
1356532	NM_001371596.2(MFSD8):c.1064T>G (p.Leu355Ter)	Pathogenic
1394953	NM_001371596.2(MFSD8):c.690dup (p.Ile231fs)	Pathogenic
1453415	NM_001371596.2(MFSD8):c.65_66del (p.Glu22fs)	Pathogenic
1455411	NM_001371596.2(MFSD8):c.1090del (p.Ile364fs)	Pathogenic
1456161	NM_001371596.2(MFSD8):c.1229dup (p.Tyr410Ter)	Pathogenic
1458681	NC_000004.11:g.(?128864897)(128886298_?)del	Pathogenic
1459550	NM_001371596.2(MFSD8):c.932_935dup (p.Leu313fs)	Pathogenic
1459614	NC_000004.11:g.(?128878646)(128878757_?)del	Pathogenic
1459891	NC_000004.11:g.(?128878646)(128886298_?)del	Pathogenic
1460410	NC_000004.11:g.(?128841775)(128878757_?)del	Pathogenic
162379	NM_001371596.2(MFSD8):c.1141G>T (p.Glu381Ter)	Pathogenic
162380	NM_001371596.2(MFSD8):c.1102G>C (p.Asp368His)	Pathogenic
162381	NM_001371596.2(MFSD8):c.863+3_863+4insT	Pathogenic
1685948	NM_001371596.2(MFSD8):c.362_363del (p.Tyr121fs)	Pathogenic
1697236	NM_001371596.2(MFSD8):c.699-1G>A	Pathogenic
1802252	NM_001371596.2(MFSD8):c.742_746del (p.Ile247_Asn248insTer)	Pathogenic

SpliceAI

2489 predictions. Top by Δscore:

Variant	Effect	Δscore
4:127921591:AAT:A	donor_gain	1.0000
4:127921862:T:A	donor_gain	1.0000
4:127930677:A:C	donor_gain	1.0000
4:127930681:A:AC	donor_gain	1.0000
4:127930682:C:CC	donor_gain	1.0000
4:127930682:CT:C	donor_gain	1.0000
4:127930700:AACT:A	donor_gain	1.0000
4:127930701:A:C	donor_gain	1.0000
4:127930813:TGATG:T	acceptor_gain	1.0000
4:127930818:C:CC	acceptor_gain	1.0000
4:127932983:A:AC	donor_gain	1.0000
4:127932984:C:CC	donor_gain	1.0000
4:127933090:CTTG:C	acceptor_gain	1.0000
4:127933091:TTG:T	acceptor_gain	1.0000
4:127933094:C:CC	acceptor_gain	1.0000
4:127938840:T:C	acceptor_gain	1.0000
4:127918391:T:TG	acceptor_gain	0.9900
4:127921767:CAAAT:C	acceptor_gain	0.9900
4:127921771:TC:T	acceptor_loss	0.9900
4:127921772:C:CA	acceptor_loss	0.9900
4:127921772:C:CC	acceptor_gain	0.9900
4:127921773:T:A	acceptor_loss	0.9900
4:127921861:TTCCC:T	donor_gain	0.9900
4:127930677:ACTT:A	donor_loss	0.9900
4:127930679:TTA:T	donor_loss	0.9900
4:127930680:TA:T	donor_loss	0.9900
4:127930681:A:T	donor_loss	0.9900
4:127930682:C:A	donor_loss	0.9900
4:127930682:CTT:C	donor_gain	0.9900
4:127930682:CTTT:C	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000042677 (4:127919420 T>C,G), RS1000049259 (4:127936236 C>A), RS1000055227 (4:127931252 C>T), RS1000063026 (4:127963768 A>G), RS1000107899 (4:127917698 G>A,T), RS1000154520 (4:127929361 A>G), RS1000235613 (4:127954569 T>C), RS1000265227 (4:127954936 T>C,G), RS1000335057 (4:127932459 A>G), RS1000425367 (4:127951012 A>G), RS1000502166 (4:127941347 T>C), RS1000572297 (4:127961954 G>GAC), RS1000575410 (4:127957142 G>A), RS1000582604 (4:127941620 C>A,T), RS1000634083 (4:127952202 G>A)

Disease associations

OMIM: gene MIM:611124 | disease phenotypes: MIM:610951, MIM:616170, MIM:256730, MIM:608716, MIM:120970, MIM:248200, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	Autosomal recessive
neuronal ceroid lipofuscinosis 7	Definitive	Autosomal recessive
macular dystrophy with central cone involvement	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Mondo (14): neuronal ceroid lipofuscinosis 7 (MONDO:0012588), late infantile neuronal ceroid lipofuscinosis (MONDO:0015674), macular dystrophy with central cone involvement (MONDO:0014515), neuronal ceroid lipofuscinosis (MONDO:0016295), congenital nervous system disorder (MONDO:0002320), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), retinal disorder (MONDO:0005283), microcephaly 5, primary, autosomal recessive (MONDO:0012106), cone-rod dystrophy (MONDO:0015993), severe early-childhood-onset retinal dystrophy (MONDO:0009549), retinitis pigmentosa (MONDO:0019200), hereditary ataxia (MONDO:0100309), intellectual disability (MONDO:0001071)

Orphanet (12): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN7 disease (Orphanet:228366), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Autosomal recessive primary microcephaly (Orphanet:2512), Cone rod dystrophy (Orphanet:1872), Severe early-childhood-onset retinal dystrophy (Orphanet:364055), Retinitis pigmentosa (Orphanet:791), Stargardt disease (Orphanet:827), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000580	Pigmentary retinopathy
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000642	Red-green dyschromatopsia
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000750	Delayed speech and language development
HP:0001105	Retinal atrophy
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0002059	Cerebral atrophy
HP:0002123	Generalized myoclonic seizure
HP:0002180	Neurodegeneration
HP:0002353	EEG abnormality
HP:0002360	Sleep disturbance
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003678	Rapidly progressive
HP:0007641	Dyschromatopsia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002726_28	Glucose homeostasis traits	5.000000e-07
GCST002726_35	Glucose homeostasis traits	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C563989	Ceroid Lipofuscinosis, Neuronal, 7 (supp.)
C531684	Hereditary spinal ataxia (supp.)
C563871	Microcephaly, Primary Autosomal Recessive, 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression, increases expression, increases methylation	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Coal	decreases expression, increases abundance	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Phthalic Acids	decreases methylation	1
Quercetin	decreases expression	1
Smoke	decreases expression, increases abundance	1
Oxyquinoline	decreases expression	1
Copper Sulfate	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases expression	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D4GU	HCT116-MFSD8-KO-c2	Cancer cell line	Male
CVCL_D4GV	HCT116-MFSD8-KO-c22	Cancer cell line	Male
CVCL_D5F1	HeLa::TMEM192-3xHA MFSD8 KO	Cancer cell line	Female
CVCL_D7GZ	Ubigene HEK293T MFSD8 KO	Transformed cell line	Female
CVCL_E0HZ	Ubigene HeLa MFSD8 KO	Cancer cell line	Female
CVCL_F0Q1	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) MFSD8-/-	Embryonic stem cell	Female
CVCL_SY22	HAP1 MFSD8 (-) 1	Cancer cell line	Male
CVCL_XQ49	HAP1 MFSD8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT02678689	PHASE2	COMPLETED	A Safety, Tolerability, and Efficacy Study of BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT04489511	PHASE2	COMPLETED	Study of STG-001 in Subjects With Stargardt Disease
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa