CTNS

Summary

CTNS (cystinosin, lysosomal cystine transporter, HGNC:2518) is a protein-coding gene on chromosome 17p13.2, encoding Cystinosin (O60931). Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes.

This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1497 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cystinosis (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 954 total — 132 pathogenic, 71 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004937

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2518
Approved symbol	CTNS
Name	cystinosin, lysosomal cystine transporter
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	CTNS-LSB, PQLC4, SLC66A4
Ensembl gene	ENSG00000040531
Ensembl biotype	protein_coding
OMIM	606272
Entrez	1497

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000046640, ENST00000381870, ENST00000399306, ENST00000452111, ENST00000467663, ENST00000488623, ENST00000495445, ENST00000574218, ENST00000574776, ENST00000576979, ENST00000673669, ENST00000673965, ENST00000901058, ENST00000941477, ENST00000941478

RefSeq mRNA: 7 — MANE Select: NM_004937 NM_001031681, NM_001374492, NM_001374493, NM_001374494, NM_001374495, NM_001374496, NM_004937

CCDS: CCDS11031, CCDS32530, CCDS92228

Canonical transcript exons

ENST00000046640 — 12 exons

Exon	Start	End
ENSE00000430753	3659858	3659975
ENSE00000535517	3660236	3663103
ENSE00000669781	3656487	3656586
ENSE00000669782	3656676	3656795
ENSE00001196712	3658005	3658175
ENSE00001391410	3637107	3637316
ENSE00001952163	3636760	3636831
ENSE00003534194	3640188	3640267
ENSE00003616169	3654998	3655101
ENSE00003638757	3655221	3655352
ENSE00003684730	3647444	3647522
ENSE00003786969	3648847	3648931

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 91.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.0206 / max 193.3725, expressed in 1807 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158878	7.6854	1743
158877	6.6420	1753
158875	2.3143	1431
158876	0.3789	183

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	91.58	gold quality
left adrenal gland cortex	UBERON:0035825	91.30	gold quality
right adrenal gland	UBERON:0001233	91.24	gold quality
left adrenal gland	UBERON:0001234	91.01	gold quality
body of pancreas	UBERON:0001150	90.86	gold quality
right uterine tube	UBERON:0001302	90.84	gold quality
right testis	UBERON:0004534	90.16	gold quality
tibial nerve	UBERON:0001323	90.11	gold quality
metanephros cortex	UBERON:0010533	90.04	gold quality
left testis	UBERON:0004533	89.94	gold quality
endocervix	UBERON:0000458	89.62	gold quality
adrenal cortex	UBERON:0001235	89.45	gold quality
body of stomach	UBERON:0001161	89.38	gold quality
stromal cell of endometrium	CL:0002255	89.17	gold quality
adrenal gland	UBERON:0002369	89.10	gold quality
adrenal tissue	UBERON:0018303	88.44	gold quality
right ovary	UBERON:0002118	88.18	gold quality
mucosa of stomach	UBERON:0001199	88.14	gold quality
testis	UBERON:0000473	88.10	gold quality
ectocervix	UBERON:0012249	87.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.93	gold quality
upper lobe of left lung	UBERON:0008952	86.91	gold quality
left ovary	UBERON:0002119	86.80	gold quality
stomach	UBERON:0000945	86.57	gold quality
gastrocnemius	UBERON:0001388	86.47	gold quality
sural nerve	UBERON:0015488	86.43	gold quality
apex of heart	UBERON:0002098	86.28	gold quality
granulocyte	CL:0000094	86.25	gold quality
pancreas	UBERON:0001264	86.23	gold quality
body of uterus	UBERON:0009853	86.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.74
E-MTAB-6386	no	348.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

76 targeting CTNS, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-609	99.82	64.26	505
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• specific promotor mutations cause cystinosis (PMID:11505338)
• G339R mutation is a common cause of nephropathic cystinosis in the southwestern Ontario Amish Mennonite population (PMID:11565547)
• A new homozygous GT–>CC substitution of CTNS creates the out-of-frame splicing of exon 5 and a null allele consistent with the patient’s severe phenotype. (PMID:11708862)
• molecular basis of cystinosis - review. (PMID:12401840)
• Data suggest that these individuals carry mutations either in the introns or in unidentified regulatory sequences. (PMID:12442267)
• a 57-kb deletion in CTNS causing cystinosis can be visualized by FISH technique (PMID:15365816)
• Results show that the yeast Ers1 protein and cystinosin are functional orthologues, despite sharing only limited sequence homology. (PMID:15885099)
• There may be an influence of the cystinosis gene on brain development, rather than an adverse effect of prolonged cystine accumulation in the brain during childhood. (PMID:17643777)
• Analysis of the CTNS gene in nephrotic cystinosis Mexian patients: report of four novel mutations and identification of a false-positive 57-kb deletion genotype with LDM-2/exon 4 multiplex PCR assay. (PMID:18752449)
• Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 3-bp in-frame deletion in exon 10 (c.809_811delCCT), resulting in the loss of a conserved p.Ser270del within the fifth transmembrane domain of CTNS. (PMID:19580442)
• Eight mutations were identified, four of which are novel (c.530A>G, c.681G>A, 1013T>G, and c.1018_1041del). These alleles will provide the basis for routine molecular diagnosis of cystinosis. (PMID:19852576)
• Analysis of the CTNS gene in 32 cystinosis patients from Spain (PMID:19863563)
• gene expression is modulated by intracellular thiols (PMID:20079424)
• Analysis of CTNS gene transcripts allowed identification of mutations in patients in whom CTNS mutations could not be detected by traditional DNA sequencing. (PMID:20352457)
• the cause of cellular ATP depletion in nephrotic cystinosis may be the futile cycle, formed between two ATP-dependant gamma-glutamyl cycle enzymes, gamma-glutamyl cysteine synthetase and 5-oxoprolinase (PMID:20413906)
• CTNS plays a pivotal role in regulating cell thiol concentrations. (PMID:21508882)
• Report CTNS mutations in Turkish cystinosis patients. (PMID:21786142)
• cystinosin exports the proteolysis-derived dimeric amino acid cystine from lysosomes and is impaired in cystinosis. (PMID:22232659)
• Cystinosin, MPDU1, SWEETs and KDELR belong to a well-defined protein family with putative function of cargo receptors.[cytonosin] (PMID:22363504)
• Mutation analysis of CTNS in six cystinosis patients from four families in Thailand. Using PCR sequencing of the entire coding regions, study identified all eight mutant alleles, including two mutations, p.G309D and p.Q284X, that have not been previously reported. (PMID:22450360)
• CTNS-LKG represents 5-20 % of CTNS transcripts, with the exception of the testis that expresses both isoforms in equal proportions. (PMID:22544350)
• results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation (PMID:22649030)
• The present data exhibit a fundament for molecular carrier detection and prenatal diagnosis of a relatively large percentage of Iranian patients suffering from NC (PMID:23640116)
• We recommend that black South African and Cape Coloured patients presenting with cystinosis be tested for CTNS-c.971-12G > A in the first instance, with the possibility of prenatal testing being offered to at-risk families. (PMID:25326109)
• cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. (PMID:25811383)
• identified two novel CTNS splicing deletions in a Chinese IC family, one at the donor site of exon 6 of CTNS and the other at the acceptor site of exon 8 (PMID:25866837)
• The coding exons of the CTNS gene in 5 different Jordanian families and one family from Sudan with nephropathic cystinosis were sequenced. None had the European 57-kb deletion. 7 variants in the coding and promoter sequence of the CTNS gene were found: 294C>T, -180T>C, -118C>T, c.504G>A, p.Thr168Thr, c.829dupA in exon 10, and c.890G>A in exon 11. (PMID:26565940)
• Using polymerase chain reaction sequencing of the entire coding region, we identified five gene mutations, including two unreported mutations. (PMID:26655004)
• Lack of cystinosin reduced TFEB expression and induced TFEB nuclear translocation. (PMID:26994576)
• CTNS deficiency alters cell signaling cascades resulting in impaired cell adhesion and enhanced cell motility in cystinosis. (PMID:27083281)
• silencing of AP-2 triggers the clathrin-independent endocytosis, showing the complex adaptability of cystinosin-LKG trafficking (PMID:27148969)
• GCK mutations are associated with Cystinosis. (PMID:27269891)
• This work demonstrated no major abnormality ofER and lysosomal Ca2+signalling associated with cystinosin defi-ciency in human proximal tubular epithelial cells. (PMID:27451386)
• To study the role of the cystinosin-LKG-isoform, we have investigated cystine accumulation and apoptosis that have been described in cystinotic cells. The levels of TNFalpha- and actinomycin D-inducted apoptosis dropped in cystinotic cells expressing LKG-isoform. This effect was also similar to the main isoform. (PMID:27656773)
• Results show that the high turnover of ITILELP mutation (del AA67-73) in cystinosin, because of its immature glycosylation state together with low transport activity, might be responsible for the phenotype observed in some cystinosis patients who carry this mutation. (PMID:28082515)
• Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS (PMID:28238446)
• upon comparison of the patients with cystinosis in this particular region with the European and North American patients, it is clear that different CTNS variants result in this disease. (PMID:28276207)
• Potential dual function of PQ-loop proteins such as cystinosin. (PMID:28887435)
• Human cystinosin expressed in this yeast confers growth on cystine when the protein is mistargeted to the plasma membrane by the deletion of the C-terminal targeting signal, GYQDL. (PMID:29467429)
• CTNS gene mutation is associated with cystinosis. (PMID:30849045)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctns	ENSDARG00000008890
mus_musculus	Ctns	ENSMUSG00000005949
rattus_norvegicus	Ctns	ENSRNOG00000028688
drosophila_melanogaster	Ctns	FBGN0039045
caenorhabditis_elegans		WBGENE00008052

Protein

Protein identifiers

Cystinosin — O60931 (reviewed: O60931)

All UniProt accessions (11): A0A0S2Z3I9, A0A0S2Z3K3, A0A669KAZ5, A0A669KB82, A8MXW3, O60931, C9JMM9, I3L0Z6, I3L1K8, I3L484, I3L4A9

UniProt curated annotations — full annotation on UniProt →

Function. Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes. Plays an important role in melanin synthesis by catalyzing cystine export from melanosomes, possibly by inhibiting pheomelanin synthesis. In addition to cystine export, also acts as a positive regulator of mTORC1 signaling in kidney proximal tubular cells, via interactions with components of the v-ATPase and Ragulator complexes. Also involved in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, independently of cystine transporter activity.

Subunit / interactions. Interacts with components of the V-ATPase complex. Interacts with components of the Ragulator complex. Interacts with RRAGA/RagA and RRAGC/RagC. Interacts with AP-3 complex subunit mu (AP3M1 or AP3M2).

Subcellular location. Lysosome membrane. Melanosome membrane Lysosome membrane. Cell membrane.

Tissue specificity. Strongly expressed in pancreas, kidney (adult and fetal), skeletal muscle, melanocytes and keratinocytes. Expressed at lower levels in placenta and heart. Weakly expressed in lung, liver and brain (adult and fetal). Represents 5-20 % of CTNS transcripts, with the exception of the testis that expresses both isoforms in equal proportions.

Disease relevance. Cystinosis, nephropathic type (CTNS) [MIM:219800] A form of cystinosis, a lysosomal storage disease due to defective transport of cystine across the lysosomal membrane. This results in cystine accumulation and crystallization in the cells causing widespread tissue damage. The classical nephropathic form has onset in the first year of life and is characterized by a polyuro-polydipsic syndrome, marked height-weight growth delay, generalized impaired proximal tubular reabsorptive capacity, with severe fluid-electrolyte balance alterations, renal failure, ocular symptoms and other systemic complications. The disease is caused by variants affecting the gene represented in this entry. Cystinosis, adult, non-nephropathic type (CTNSANN) [MIM:219750] A form of cystinosis, a lysosomal storage disease due to defective transport of cystine across the lysosomal membrane. This results in cystine accumulation and crystallization in the cells causing widespread tissue damage. Cystinosis adult non-nephropathic type is characterized by ocular features and a benign course. Patients manifest mild photophobia due to conjunctival and corneal cystine crystals. The disease is caused by variants affecting the gene represented in this entry. Cystinosis, late-onset juvenile or adolescent nephropathic type (CTNSJAN) [MIM:219900] A form of cystinosis, a lysosomal storage disease due to defective transport of cystine across the lysosomal membrane. This results in cystine accumulation and crystallization in the cells causing widespread tissue damage. Late-onset juvenile or adolescent nephropathic cystinosis is an intermediated form, manifesting first at age 10 to 12 years with proteinuria due to glomerular damage rather than with the manifestations of tubular damage that occur first in infantile cystinosis. There is no excess amino aciduria and stature is normal. Photophobia, late development of pigmentary retinopathy, and chronic headaches are features. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Switches between a lumen- and a cytosol-open conformation: pH induces conformational changes and shifts the equilibrium to facilitate the transition between the lumen- and cytosol-open conformation, thereby promoting cystine transport. Protonation of specific aspartate residues (Asp-205, Asp-305 and Asp-346) favors the cytosol-open conformation.

Domain organisation. The lysosomal targeting motif, together with the second PQ-loop mediate targeting to the lysosome.

Similarity. Belongs to the cystinosin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60931-1	1	yes
O60931-2	2, cystinosin-LKG

RefSeq proteins (7): NP_001026851, NP_001361421, NP_001361422, NP_001361423, NP_001361424, NP_001361425, NP_004928* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005282	LC_transporter	Family
IPR006603	PQ-loop_rpt	Repeat

Pfam: PF04193

Catalyzed reactions (Rhea), 1 shown:

• L-cystine(out) + H(+)(out) = L-cystine(in) + H(+)(in) (RHEA:66172)

UniProt features (143 total): sequence variant 41, mutagenesis site 38, strand 14, helix 9, binding site 9, topological domain 8, transmembrane region 7, glycosylation site 7, turn 4, domain 2, signal peptide 1, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8DKX	ELECTRON MICROSCOPY	3
8DKW	ELECTRON MICROSCOPY	3.09
8DKE	ELECTRON MICROSCOPY	3.18
8DKI	ELECTRON MICROSCOPY	3.32
8DKM	ELECTRON MICROSCOPY	3.39
8DYP	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60931-F1	89.27	0.75

Antibody-complex structures (SAbDab): 6 — 8DKE, 8DKI, 8DKM, 8DKW, 8DKX, 8DYP

Functional residue map

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

Ligand- & substrate-binding residues (9): 166; 205; 273; 280; 281; 301; 305 (protonated residue following cystine-binding); 305; 346

Glycosylation sites (7): 36, 41, 51, 66, 84, 104, 107

Mutagenesis-validated functional residues (38):

Position	Phenotype
289–298	in delta(b) mutant; does not abolish localization to the lysosome; when associated with deletion of 362-g–l-366.
301	strongly decreased cystine transport.
305	abolished steady-state transport current.
305	abolished cystine transport. abolished transient cxurrents. abolished steady-state transport current.
309	gain-of-function mutant that shows higher transport of cystine.
312	gain-of-function mutant that shows higher transport of cystine.
319	strongly decreased cystine transport.
335	nearly abolished cystine transport.
335	abolished steady-state transport current. decreased midpoint potential. impaired dielectric distance. accelerated the ti
362–366	strongly reduced but not abolished localization to the lysosome, leading to partial relocation to the cell membrane. abo
362	does not affect localization to the lysosome.
363	strongly reduced but not abolished localization to the lysosome, leading to partial relocation to the cell membrane.
364	does not affect localization to the lysosome.
365	does not affect localization to the lysosome.
366	strongly reduced but not abolished localization to the lysosome, leading to partial relocation to the cell membrane.
396–400	abolished localization to the cell membrane. does not affect cystine transport.
66	decreased glycosylation.
131	gain-of-function mutant that shows higher transport of cystine.
134	nearly abolished cystine transport.
137	gain-of-function mutant that shows higher transport of cystine.
138	abolished cystine transport.
142	abolished cystine transport.
143	slightly decreased midpoint potential. impaired dielectric distance.
145	increased cystine uptake activity.
152	impaired dielectric distance.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-9959399	SLC-mediated transport of oligopeptides
R-HSA-425393

MSigDB gene sets: 433 (showing top): GOBP_MEMORY, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_COGNITION, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GOCC_VACUOLAR_MEMBRANE, GOBP_ADULT_BEHAVIOR, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GOBP_ASSOCIATIVE_LEARNING, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, KEGG_LYSOSOME, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (22): lens development in camera-type eye (GO:0002088), amino acid metabolic process (GO:0006520), glutathione metabolic process (GO:0006749), monoatomic ion transport (GO:0006811), brain development (GO:0007420), long-term memory (GO:0007616), grooming behavior (GO:0007625), adult walking behavior (GO:0007628), visual learning (GO:0008542), protein transport (GO:0015031), L-cystine transport (GO:0015811), melanin biosynthetic process (GO:0042438), ATP metabolic process (GO:0046034), regulation of melanin biosynthetic process (GO:0048021), cognition (GO:0050890), transmembrane transport (GO:0055085), regulation of TORC1 signaling (GO:1903432), positive regulation of TORC1 signaling (GO:1904263), animal organ development (GO:0048513), system development (GO:0048731), L-alpha-amino acid transmembrane transport (GO:1902475), proton transmembrane transport (GO:1902600)

GO Molecular Function (5): L-cystine transmembrane transporter activity (GO:0015184), solute:proton symporter activity (GO:0015295), protein binding (GO:0005515), L-amino acid transmembrane transporter activity (GO:0015179), symporter activity (GO:0015293)

GO Cellular Component (9): lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), plasma membrane (GO:0005886), melanosome membrane (GO:0033162), melanosome (GO:0042470), extracellular exosome (GO:0070062), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transport of small molecules	1
SLC-mediated transmembrane transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
transport	3
TORC1 signaling	2
cellular anatomical structure	2
camera-type eye development	1
primary metabolic process	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
central nervous system development	1
animal organ development	1
head development	1
memory	1
behavior	1
adult locomotory behavior	1
walking behavior	1
visual behavior	1
associative learning	1
intracellular protein localization	1
establishment of protein localization	1
sulfur amino acid transport	1
neutral amino acid transport	1
L-amino acid transport	1
modified amino acid transport	1
melanin metabolic process	1
secondary metabolite biosynthetic process	1
pigment biosynthetic process	1
phenol-containing compound biosynthetic process	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
melanin biosynthetic process	1
regulation of secondary metabolite biosynthetic process	1
nervous system process	1
cellular process	1
regulation of TOR signaling	1
positive regulation of TOR signaling	1
regulation of TORC1 signaling	1
multicellular organism development	1
sulfur amino acid transmembrane transporter activity	1
L-amino acid transmembrane transporter activity	1
L-cystine transport	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTNS	SHPK	Q9UHJ6	976
CTNS	SLC66A1	Q6ZP29	811
CTNS	FGGY	Q96C11	711
CTNS	TRPV1	Q8NER1	711
CTNS	TNNI3	P19429	621
CTNS	TNNT2	P45379	594
CTNS	CLN3	Q13286	592
CTNS	SLC17A5	Q9NRA2	521
CTNS	RRAGC	Q9HB90	500
CTNS	IDUA	P35475	483
CTNS	TRPA1	O75762	475
CTNS	OCRL	Q01968	463
CTNS	CLCN5	P51795	461
CTNS	YBX3	P16989	460
CTNS	LRP2	P98164	454

IntAct

1 interactions, top by confidence:

BioGRID (11): CTNS (Synthetic Lethality), GNMT (Two-hybrid), CTNS (Affinity Capture-RNA), CTNS (Positive Genetic), CTNS (Co-fractionation), CTNS (Co-fractionation), ENPP4 (Co-fractionation), FZD1 (Co-fractionation), IFITM2 (Co-fractionation), IFITM3 (Co-fractionation), CTNS (Affinity Capture-RNA)

ESM2 similar proteins: A2WR31, A2X5B4, A2XGM7, A7MB63, A8XI14, B8A833, B8BKP4, O45102, O60931, O82587, P0DKJ4, P0DKJ5, P57757, P93332, Q02334, Q0D2K0, Q0DJY3, Q10482, Q10LI8, Q19VE6, Q290X1, Q2QR07, Q2R3P9, Q54JW5, Q5JJY5, Q5N8J1, Q5NAZ9, Q6K602, Q6L568, Q6NQN5, Q6YZF3, Q7JVE7, Q7RTP0, Q84WN3, Q8BHK1, Q8BZF2, Q8LBF7, Q8LFH5, Q944M5, Q95XZ6

Diamond homologs: A7MB63, A8WN56, O60931, P17261, P57757, P57758, Q09500, Q54WT7, Q9VCR7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	132
Likely pathogenic	71
Uncertain significance	263
Likely benign	324
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065827	NM_004937.3(CTNS):c.681+8del	Pathogenic
1068522	NM_004937.3(CTNS):c.140+1del	Pathogenic
1069102	NM_004937.3(CTNS):c.82_83del (p.Val28fs)	Pathogenic
1069679	NC_000017.10:g.(?3539712)(3543571_?)del	Pathogenic
1069680	NC_000017.10:g.(?3539712)(3552235_?)del	Pathogenic
1071434	NM_004937.3(CTNS):c.274C>T (p.Gln92Ter)	Pathogenic
1076859	NM_004937.3(CTNS):c.735G>A (p.Trp245Ter)	Pathogenic
1179166	GRCh37/hg19 17p13.2(chr17:3539741-3561489)	Pathogenic
1362222	NM_004937.3(CTNS):c.539_551del (p.Leu180fs)	Pathogenic
1391189	NM_004937.3(CTNS):c.1A>T (p.Met1Leu)	Pathogenic
1395082	NM_004937.3(CTNS):c.449G>A (p.Trp150Ter)	Pathogenic
1425663	NM_004937.3(CTNS):c.699_700del (p.Ser234fs)	Pathogenic
1451995	NM_004937.3(CTNS):c.668del (p.Cys223fs)	Pathogenic
1455393	NM_004937.3(CTNS):c.922G>C (p.Gly308Arg)	Pathogenic
1456035	NC_000017.10:g.(?3550728)(3550826_?)del	Pathogenic
1457577	NM_004937.3(CTNS):c.152_153insCT (p.Ala52fs)	Pathogenic
1458479	NC_000017.10:g.(?3504346)(3561464_?)del	Pathogenic
1459518	NC_000017.11:g.3659858del	Pathogenic
1705665	NM_004937.3(CTNS):c.751_752del (p.Thr251fs)	Pathogenic
188714	NM_004937.3(CTNS):c.926dup (p.Ser310fs)	Pathogenic
188718	NM_004937.3(CTNS):c.611ACG[1] (p.Asp205del)	Pathogenic
188741	NM_004937.3(CTNS):c.292dup (p.Thr98fs)	Pathogenic
188834	NM_004937.3(CTNS):c.18_21del (p.Thr7fs)	Pathogenic
2009652	NM_004937.3(CTNS):c.85_86del (p.Pro29fs)	Pathogenic
2017872	NC_000017.11:g.3660238_3660245del	Pathogenic
2091086	NM_004937.3(CTNS):c.936_945del (p.Ser312fs)	Pathogenic
2137880	NM_004937.3(CTNS):c.923G>T (p.Gly308Val)	Pathogenic
21440	NM_004937.3(CTNS):c.613G>A (p.Asp205Asn)	Pathogenic
21441	NM_004937.3(CTNS):c.696dup (p.Val233fs)	Pathogenic
2194886	NM_004937.3(CTNS):c.141-24T>C	Pathogenic

SpliceAI

2206 predictions. Top by Δscore:

Variant	Effect	Δscore
17:3647432:G:A	acceptor_gain	1.0000
17:3647520:GCG:G	donor_gain	1.0000
17:3647522:GGTAA:G	donor_loss	1.0000
17:3647523:G:GG	donor_gain	1.0000
17:3647524:TAA:T	donor_loss	1.0000
17:3656476:A:AG	acceptor_gain	1.0000
17:3656477:C:G	acceptor_gain	1.0000
17:3656484:CAGTG:C	acceptor_loss	1.0000
17:3656485:A:AG	acceptor_gain	1.0000
17:3656485:AGT:A	acceptor_gain	1.0000
17:3656486:G:GA	acceptor_gain	1.0000
17:3656486:GT:G	acceptor_gain	1.0000
17:3656486:GTG:G	acceptor_gain	1.0000
17:3656486:GTGTC:G	acceptor_gain	1.0000
17:3656582:TCAAG:T	donor_loss	1.0000
17:3656583:CAAGG:C	donor_loss	1.0000
17:3656584:AAG:A	donor_loss	1.0000
17:3656587:GT:G	donor_loss	1.0000
17:3656588:T:A	donor_loss	1.0000
17:3656674:A:AG	acceptor_gain	1.0000
17:3656675:G:GG	acceptor_gain	1.0000
17:3656793:GAG:G	donor_gain	1.0000
17:3656793:GAGGT:G	donor_loss	1.0000
17:3656794:AGGTG:A	donor_loss	1.0000
17:3656796:G:GG	donor_gain	1.0000
17:3659842:C:CA	acceptor_gain	1.0000
17:3659846:T:TA	acceptor_gain	1.0000
17:3659850:T:TA	acceptor_gain	1.0000
17:3659851:G:A	acceptor_gain	1.0000
17:3659972:AACGG:A	donor_loss	1.0000

AlphaMissense

2426 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:3655303:T:A	W138R	0.997
17:3655303:T:C	W138R	0.997
17:3656545:A:C	S174R	0.997
17:3656547:T:A	S174R	0.997
17:3656547:T:G	S174R	0.997
17:3656739:A:C	S209R	0.997
17:3656741:C:A	S209R	0.997
17:3656741:C:G	S209R	0.997
17:3659920:C:A	D305E	0.996
17:3659920:C:G	D305E	0.996
17:3659939:A:C	S312R	0.996
17:3659941:C:A	S312R	0.996
17:3659941:C:G	S312R	0.996
17:3659894:T:A	W297R	0.995
17:3659894:T:C	W297R	0.995
17:3659919:A:C	D305A	0.995
17:3659919:A:T	D305V	0.995
17:3659869:C:A	N288K	0.994
17:3659869:C:G	N288K	0.994
17:3659919:A:G	D305G	0.994
17:3656533:T:C	F170L	0.993
17:3656535:C:A	F170L	0.993
17:3656535:C:G	F170L	0.993
17:3659918:G:C	D305H	0.993
17:3656551:T:C	F176L	0.992
17:3656553:C:A	F176L	0.992
17:3656553:C:G	F176L	0.992
17:3656736:T:C	F208L	0.992
17:3656738:C:A	F208L	0.992
17:3656738:C:G	F208L	0.992

dbSNP variants (sampled 300 via entrez): RS1000052522 (17:3643716 G>A), RS1000067853 (17:3659591 C>T), RS1000097396 (17:3651352 C>G,T), RS1000155941 (17:3638234 T>G), RS1000217819 (17:3646203 G>A), RS1000271657 (17:3646003 C>G,T), RS1000403630 (17:3643528 A>G), RS1000781207 (17:3655520 C>G,T), RS1000814886 (17:3640366 C>G,T), RS1000849967 (17:3650930 G>A), RS1000999309 (17:3660142 T>C,G), RS1001010942 (17:3650402 A>C,T), RS1001076691 (17:3660012 T>C,G), RS1001226869 (17:3644679 T>C), RS1001507172 (17:3650071 T>G)

Disease associations

OMIM: gene MIM:606272 | disease phenotypes: MIM:219750, MIM:219900, MIM:219800

GenCC curated gene-disease

Disease	Classification	Inheritance
nephropathic cystinosis	Definitive	Autosomal recessive
cystinosis	Definitive	Autosomal recessive
ocular cystinosis	Strong	Autosomal recessive
juvenile nephropathic cystinosis	Strong	Autosomal recessive
nephropathic infantile cystinosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cystinosis	Definitive	AR

Mondo (6): ocular cystinosis (MONDO:0009064), juvenile nephropathic cystinosis (MONDO:0009066), cystinosis (MONDO:0016239), nephropathic cystinosis (MONDO:0100151), nephropathic infantile cystinosis (MONDO:0018467), nephrotic syndrome (MONDO:0005377)

Orphanet (4): Cystinosis (Orphanet:213), Infantile nephropathic cystinosis (Orphanet:411629), Juvenile nephropathic cystinosis (Orphanet:411634), Ocular cystinosis (Orphanet:411641)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000026	Male hypogonadism
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000103	Polyuria
HP:0000114	Proximal tubulopathy
HP:0000117	Renal phosphate wasting
HP:0000124	Renal tubular dysfunction
HP:0000479	Abnormal retinal morphology
HP:0000481	Abnormal cornea morphology
HP:0000488	Retinopathy
HP:0000495	Recurrent corneal erosions
HP:0000505	Visual impairment
HP:0000531	Corneal crystals
HP:0000580	Pigmentary retinopathy
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000787	Nephrolithiasis
HP:0000790	Hematuria
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000832	Primary hypothyroidism
HP:0000897	Rachitic rosary
HP:0000966	Hypohidrosis
HP:0001010	Hypopigmentation of the skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001507	Growth abnormality

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010396_15	Gut microbiota (bacterial taxa, hurdle binary method)	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003554	Cystinosis	C16.320.565.595.377; C18.452.648.595.377
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C535335	Abderhalden-Kaufmann-Lignac syndrome (supp.)
C562683	Cystinosis, Late-Onset Juvenile or Adolescent Nephropathic Type (supp.)
C535765	Cystinosis, ocular nonnephropathic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630803 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC66 Lysosomal amino acid transporters

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	3
Cyclosporine	decreases expression, increases expression	3
bisphenol A	increases expression, affects expression	2
sodium arsenite	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
yessotoxin	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
jinfukang	increases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	increases expression	1
PP242	decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Lead	decreases expression	1
Methapyrilene	decreases methylation	1
Smoke	decreases expression	1
Lactic Acid	decreases expression	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
CHEMBL4630264	Binding	Inhibition of human cystinosin at 30 uM relative to control	Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin. — J Med Chem

Cellosaurus cell lines

21 cell lines: 16 finite cell line, 2 transformed cell line, 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_CW97	GM02066	Finite cell line	Female
CVCL_CW98	GM00906	Finite cell line	Male
CVCL_CW99	GM00907	Finite cell line	Female
CVCL_D9CP	Ubigene HEK293 CTNS KO	Transformed cell line	Female
CVCL_F604	GM02894	Transformed cell line	Female
CVCL_IJ34	GM17885	Finite cell line	Female
CVCL_IJ37	GM08761	Finite cell line	Female
CVCL_IJ41	GM17888	Finite cell line	Male
CVCL_RM14	CET.IPS.FFCYST-500	Induced pluripotent stem cell	Male
CVCL_SK15	HAP1 CTNS (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT01000961	PHASE3	COMPLETED	Phase 3 Study of Cysteamine Bitartrate Delayed-release (RP103) Compared to Cystagon® in Patients With Cystinosis
NCT01197378	PHASE3	COMPLETED	Long-Term Safety Follow-up Study of Cysteamine Bitartrate Delayed-release Capsules (RP103)
NCT01733316	PHASE3	COMPLETED	Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis
NCT01744782	PHASE3	COMPLETED	Safety/Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Cysteamine Treatment Naive Patients With Cystinosis
NCT04125927	PHASE3	COMPLETED	Cystadrops in Pediatric Cystinosis Patients From Six Months to Less Than Two Years Old (SCOB2)
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001213	PHASE2	COMPLETED	Cysteamine Eye Drops to Treat Corneal Crystals in Cystinosis
NCT04069260	PHASE2	TERMINATED	A Phase 2 Study of ELX-02 in Patients With Nephropathic Cystinosis
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome