GLIS3

Summary

GLIS3 (GLIS family zinc finger 3, HGNC:28510) is a protein-coding gene on chromosome 9p24.2, encoding Zinc finger protein GLIS3 (Q8NEA6). Acts both as a repressor and an activator of transcription.

This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear protein with five C2H2-type zinc finger domains. This protein functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. Mutations in this gene have been associated with neonatal diabetes and congenital hypothyroidism (NDH). Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only two have been determined.

Source: NCBI Gene 169792 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neonatal diabetes mellitus with congenital hypothyroidism (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 92
• Clinical variants (ClinVar): 795 total — 6 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 39
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001042413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28510
Approved symbol	GLIS3
Name	GLIS family zinc finger 3
Location	9p24.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC33662
Ensembl gene	ENSG00000107249
Ensembl biotype	protein_coding
OMIM	610192
Entrez	169792

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 10 protein_coding, 9 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000324333, ENST00000381971, ENST00000461870, ENST00000462164, ENST00000463680, ENST00000464391, ENST00000465708, ENST00000467497, ENST00000469833, ENST00000471664, ENST00000473846, ENST00000477901, ENST00000478315, ENST00000478844, ENST00000481827, ENST00000490709, ENST00000491889, ENST00000645097, ENST00000645252, ENST00000682749, ENST00000682846, ENST00000682864, ENST00000683926, ENST00000683998

RefSeq mRNA: 2 — MANE Select: NM_001042413 NM_001042413, NM_152629

CCDS: CCDS43784, CCDS6451

Canonical transcript exons

ENST00000381971 — 11 exons

Exon	Start	End
ENSE00001227174	3824127	3828408
ENSE00001780344	4286038	4286523
ENSE00001785765	4117768	4118881
ENSE00003490236	3898691	3898835
ENSE00003567399	4125734	4125941
ENSE00003580228	3829310	3829492
ENSE00003588251	3879427	3879595
ENSE00003671023	3932360	3932470
ENSE00003673297	3937028	3937189
ENSE00003693204	3856009	3856184
ENSE00003850087	4299421	4300068

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 95.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0586 / max 274.0164, expressed in 1285 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99792	9.1800	1202
99788	1.0182	599
99785	1.0170	632
99789	0.9887	584
99791	0.9556	597
99790	0.3371	187
99787	0.2585	112
99786	0.2331	117
99779	0.0606	8
99767	0.0099	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.95	gold quality
epithelial cell of pancreas	CL:0000083	94.94	gold quality
pancreatic ductal cell	CL:0002079	94.40	gold quality
islet of Langerhans	UBERON:0000006	93.52	gold quality
cartilage tissue	UBERON:0002418	92.95	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.02	gold quality
bronchial epithelial cell	CL:0002328	91.50	gold quality
caput epididymis	UBERON:0004358	90.08	gold quality
bronchus	UBERON:0002185	89.99	gold quality
sural nerve	UBERON:0015488	89.48	gold quality
oviduct epithelium	UBERON:0004804	88.78	gold quality
kidney epithelium	UBERON:0004819	87.69	gold quality
seminal vesicle	UBERON:0000998	86.48	gold quality
stromal cell of endometrium	CL:0002255	86.23	gold quality
pancreas	UBERON:0001264	84.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.47	gold quality
sperm	CL:0000019	83.60	silver quality
gall bladder	UBERON:0002110	83.42	gold quality
fallopian tube	UBERON:0003889	83.08	gold quality
endometrium	UBERON:0001295	82.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.78	gold quality
thyroid gland	UBERON:0002046	82.68	gold quality
renal medulla	UBERON:0000362	82.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.95	gold quality
left lobe of thyroid gland	UBERON:0001120	81.72	gold quality
right lobe of thyroid gland	UBERON:0001119	81.19	gold quality
right uterine tube	UBERON:0001302	81.16	gold quality
colonic epithelium	UBERON:0000397	80.45	gold quality
kidney	UBERON:0002113	80.39	gold quality
adult mammalian kidney	UBERON:0000082	80.24	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	4389.42
E-GEOD-180759	yes	2857.88
E-HCAD-35	yes	2696.15
E-HCAD-25	yes	23.54
E-ANND-3	yes	10.95
E-GEOD-131882	no	3891.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
BGLAP	Activation
FGF18
INS	Unknown
MAFA	Unknown
NEUROG3	Unknown
PAX6	Repression
RUNX2	Activation
SPP1	Activation

JASPAR motifs

Motif	Name	Family
MA0737.1	GLIS3	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:22391303

miRNA regulators (miRDB)

243 targeting GLIS3, 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-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• results demonstrate a major role for GLIS3 in the development of pancreatic beta cells and the thyroid, eye, liver and kidney (PMID:16715098)
• Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced beta-cell function, as indicated by homeostasis model assessment of beta-cell function. (PMID:21515849)
• Glis3 interacts with Suppressor of Fused (SUFU) (PMID:21543335)
• the associations of GLIS3-rs7034200 and CRY2-rs11605924 with fasting glucose, beta cell function, and type 2 diabetes (PMID:21747906)
• Alleles of single nucleotide polymorphisms in GLIS3 and ADCY5 may confer risk of type 2 diabetes. (PMID:21949744)
• The present data suggest that altered expression of the candidate gene GLIS3 may contribute to both type 1 and 2 type diabetes by favouring beta cell apoptosis (PMID:23737756)
• analysis of a GLIS3 variant that may have a role in resistance to Japanese type 1 diabetes (PMID:23856252)
• Whole exome sequencing followed by immunohistochemistry of fibrolamellar hepatocellular carcinoma cell lines and tumors showed two structural variants resulting in fusion transcripts: DNAJB1-PRKCA and CLPTM1L-GLIS3. (PMID:25122662)
• It may play a role in a number of physiological processes controlled by Glis3. (PMID:26147758)
• New findings with GLIS3 phenotype including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. (PMID:26259131)
• we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. (PMID:27148679)
• Replication of lead type 2 diabetes mellitus SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified. (PMID:27862917)
• Individually the rs7020673 and rs10758593 SNPs are not significantly associated with T1DM but seem to interact in the predisposition for this disease. (PMID:28597135)
• Given the role of GLIS3 in transcriptional activation and repression during embryogenesis, in humans, GLIS3 mutations present with multisystem involvement that also includes renal cystic dysplasia, progressive liver fibrosis and osteopenia. Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem.[review] (PMID:28648506)
• GLIS3 polymorphism is not associated with Dermatomyositis /Polymyositis in the Chinese Han population (PMID:28846454)
• We detect a genome-wide significant association at rs10116772 with knee and/or hip total joint replacement; for allele A, an intronic variant in GLIS3, which is expressed in cartilage of osteoarthritis patients. (PMID:29436472)
• Data did not show any associations of GLI similar 3 protein (GLIS3) gene polymorphisms rs806052, rs143051164, and rs149840771 with carbohydrate metabolism disorders among patients with maturity onset diabetes of the young (MODY) and type 2 diabetes mellitus (DM2) in Russia. (PMID:29606121)
• Data show that loss of zinc finger protein GLIS3 (GLIS3) causes beta-cell death. (PMID:29992946)
• RNA interference-mediated knockdown of the Drosophila ortholog of GLIS3 in insulin-producing cells, a model for mammalian beta cells, conferred reduced insulin output. (PMID:30242153)
• Authors show that GLIS3 binds to and directly regulates the transcription of several WNT genes, including the strong posteriorizing factor WNT3A, and that inhibition of WNT signaling is sufficient to abrogate GLIS3-induced posterior specification. (PMID:30376208)
• The SNP rs3753841 in COL11A1, rs1258267 in CHAT and rs736893 in GLIS3 are associated with PACG in northern Chinese people, and the association of genetic markers manifests a tendency of ethnic diversity. Larger population-based studies are warranted to reveal additional primary angle-closure glaucoma loci and ethnic aspects of primary angle-closure glaucoma. (PMID:30399154)
• GLIS rearrangements, particularly PAX8-GLIS3, are highly prevalent in hyalinizing trabecular but not in papillary thyroid carcinoma (PMID:30648929)
• PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. (PMID:31273314)
• Rare missense variants in GLIS3 associates nominally with increased level of HbA1c and increased risk of developing type 2 diabetes. In contrast, the rare p.I28V variant associate with reduced level of fasting plasma glucose and may be protective against type 2 diabetes. (PMID:31415576)
• Evaluation of the association between five genetic variants and primary open-angle glaucoma in a Han Chinese population. (PMID:32281515)
• Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene. (PMID:32383186)
• Association study of the functional variants of the GLIS3 gene with risk of knee osteoarthritis. (PMID:32681364)
• Transcription factor GLIS3: Critical roles in thyroid hormone biosynthesis, hypothyroidism, pancreatic beta cells and diabetes. (PMID:32693112)
• Gene of the month: GLIS1-3. (PMID:32699115)
• Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism. (PMID:33667596)
• Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene. (PMID:33852861)
• Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins. (PMID:34093443)
• GLIS family zinc finger 3 promoting cell malignant behaviors and NF-kappaB signaling in glioma. (PMID:34403660)
• GLIS3: A Critical Transcription Factor in Islet beta-Cell Generation. (PMID:34943978)
• A circular RNA derived from GLIS3 accelerates the proliferation of glioblastoma cells through competitively binding with miR-449c-5p to upregulate CAPG and GLIS3. (PMID:36114444)
• Gli-similar 3 (GLIS3) rs7020763 (C>G) polymorphism in patients with type 2 diabetes mellitus. (PMID:36206155)
• GLIS Family Zinc Finger 3 Promotes Triple-Negative Breast Cancer Progression by Inducing Cell Proliferation, Migration and Invasion, and Activating the NF-kappaB Signaling Pathway. (PMID:36724950)
• GLIS3, a novel prognostic indicator of gastric adenocarcinoma, contributes to the malignant biological behaviors of tumor cells via modulating TGF-beta1/TGFbetaR1/Smad1/5 signaling pathway. (PMID:37651918)
• Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas. (PMID:38051360)
• CircGLIS3 promotes gastric cancer progression by regulating the miR-1343-3p/PGK1 pathway and inhibiting vimentin phosphorylation. (PMID:38459513)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	glis3	ENSDARG00000069726
mus_musculus	Glis3	ENSMUSG00000052942
rattus_norvegicus	Glis3	ENSRNOG00000014768

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC1 (ENSG00000152977), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein GLIS3 — Q8NEA6 (reviewed: Q8NEA6)

Alternative names: GLI-similar 3, Zinc finger protein 515

All UniProt accessions (7): Q8NEA6, A0A0S2Z689, A0A2R8YEK9, A0A804HJJ4, F8WEV9, Q1PHJ2, Q1PHJ8

UniProt curated annotations — full annotation on UniProt →

Function. Acts both as a repressor and an activator of transcription. Binds to the consensus sequence 5’-GACCACCCAC-3'.

Subcellular location. Nucleus.

Tissue specificity. In the adult, expressed at high levels in the kidney and at lower levels in the brain, skeletal muscle, pancreas, liver, lung, thymus and ovary.

Disease relevance. Diabetes mellitus, neonatal, with congenital hypothyroidism (NDH) [MIM:610199] A syndrome of neonatal diabetes syndrome associated with congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GLI C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NEA6-1	1	yes
Q8NEA6-2	2

RefSeq proteins (2): NP_001035878, NP_689842 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR043359	GLI-like	Family
IPR056436	Znf-C2H2_ZIC1-5/GLI1-3-like	Domain

Pfam: PF00096, PF23561

UniProt features (23 total): compositionally biased region 7, zinc finger region 5, region of interest 4, sequence variant 3, chain 1, short sequence motif 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEA6-F1	49.95	0.01

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 277 (showing top): GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, AAAGGGA_MIR204_MIR211, NUYTTEN_EZH2_TARGETS_DN, EVI1_02, CTGTTAC_MIR194, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, HORIUCHI_WTAP_TARGETS_UP, CHICAS_RB1_TARGETS_SENESCENT, GOBP_NEGATIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, PEDERSEN_METASTASIS_BY_ERBB2_ISOFORM_7

GO Biological Process (4): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), zinc ion binding (GO:0008270), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
DNA-binding transcription factor activity, RNA polymerase II-specific	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
DNA-templated transcription	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
transcription cis-regulatory region binding	1
nucleic acid binding	1
binding	1
cation binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLIS3	GPR152	Q8TDT2	791
GLIS3	NEUROD1	Q13562	751
GLIS3	NEUROG3	Q9Y4Z2	750
GLIS3	INHA	P05111	746
GLIS3	WWTR1	Q9GZV5	742
GLIS3	DHX9	Q08211	738
GLIS3	SLC1A1	P43005	713
GLIS3	RFX6	Q8HWS3	682
GLIS3	CLPP	Q16740	641
GLIS3	HHEX	Q03014	625
GLIS3	PTF1A	Q7RTS3	612
GLIS3	SLC30A8	Q8IWU4	603
GLIS3	ABCC8	Q09428	596
GLIS3	KCNJ11	Q14654	595
GLIS3	C2CD4B	A6NLJ0	595

IntAct

9 interactions, top by confidence:

A	B	Type	Score
SUFU	GLIS3	psi-mi:“MI:0915”(physical association)	0.550
CLNK	GLIS3	psi-mi:“MI:0915”(physical association)	0.490
YAP1	GLIS3	psi-mi:“MI:0407”(direct interaction)	0.440
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
GLIS3	ENO1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (42): GLIS3 (Two-hybrid), GLIS3 (Two-hybrid), ITCH (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), SUFU (Affinity Capture-MS), DNAJA1 (Affinity Capture-MS), Dnaja1 (Two-hybrid), Hipk3 (Two-hybrid), Isl1 (Two-hybrid), Itch (Two-hybrid), Kdm4c (Two-hybrid), Nedd4 (Two-hybrid), Smurf1 (Two-hybrid), Smurf2 (Two-hybrid), Spop (Two-hybrid)

ESM2 similar proteins: A0A0D1DMJ6, A0A0F0I5G4, A0A0S6XAX9, A0A1L9WQN2, A0A1U9YI06, A0A2U8U2L8, A0A345BJN6, A0A7M4BDQ2, A2QA83, A4II20, B0Y9W4, B4XXY3, B6GVZ2, B7WN96, K0DZ91, K9GKQ6, N4XMB0, O75603, P10069, P20945, P40656, P48590, Q01196, Q03347, Q05159, Q08427, Q08775, Q09602, Q09824, Q12531, Q27403, Q2U9L6, Q2UQZ5, Q4WPF5, Q4WRE4, Q4WV91, Q58L83, Q5B7I8, Q5BBM1, Q5RFT9

Diamond homologs: A0A5K4F1D0, A0JC51, A4FV57, O57311, O60481, O73689, O95409, P08151, P10070, P10071, P19538, P34708, P39768, P46684, P47806, P55878, P55879, Q0VGT2, Q15915, Q17308, Q5IS56, Q61467, Q61602, Q62520, Q62521, Q6DJQ6, Q6GR30, Q6XP49, Q6ZN18, Q7JNM3, Q7K0S9, Q7SXV2, Q7TQ40, Q8JJC0, Q8K1M4, Q8N9L1, Q8NBF1, Q8NEA6, Q8SV95, Q8VDL9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SUFU	down-regulates	GLIS3	binding
ITCH	“down-regulates quantity”	GLIS3	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	468
Likely benign	156
Benign	80

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1325	NM_001042413.2(GLIS3):c.2338dup (p.Arg780fs)	Pathogenic
253043	NM_001042413.2(GLIS3):c.1608C>G (p.Cys536Trp)	Pathogenic
253044	NM_001042413.2(GLIS3):c.1681C>T (p.His561Tyr)	Pathogenic
253045	NM_001042413.2(GLIS3):c.932del (p.Gly311fs)	Pathogenic
3694326	NM_001042413.2(GLIS3):c.662C>G (p.Ser221Ter)	Pathogenic
4085342	NM_001042413.2(GLIS3):c.484G>T (p.Gly162Ter)	Pathogenic
1338589	NM_001042413.2(GLIS3):c.728dup (p.Asn244fs)	Likely pathogenic
2502239	NM_001042413.2(GLIS3):c.122C>A (p.Ser41Ter)	Likely pathogenic
3030919	NM_001042413.2(GLIS3):c.8del (p.Gly3fs)	Likely pathogenic
3597403	NM_001042413.2(GLIS3):c.1435C>T (p.Gln479Ter)	Likely pathogenic
3597413	NM_001042413.2(GLIS3):c.1237del (p.Val413fs)	Likely pathogenic
3597439	NM_001042413.2(GLIS3):c.565del (p.Ala189fs)	Likely pathogenic
3597452	NM_001042413.2(GLIS3):c.304C>T (p.Gln102Ter)	Likely pathogenic
4719652	NM_001042413.2(GLIS3):c.597-1G>T	Likely pathogenic

SpliceAI

5357 predictions. Top by Δscore:

Variant	Effect	Δscore
9:3828404:ATACA:A	acceptor_gain	1.0000
9:3828405:TACA:T	acceptor_gain	1.0000
9:3828406:ACA:A	acceptor_gain	1.0000
9:3828407:CA:C	acceptor_gain	1.0000
9:3828407:CAC:C	acceptor_gain	1.0000
9:3828409:C:CC	acceptor_gain	1.0000
9:3898833:CAA:C	acceptor_gain	1.0000
9:3898834:AA:A	acceptor_gain	1.0000
9:3898836:C:CC	acceptor_gain	1.0000
9:3936977:T:TA	donor_gain	1.0000
9:3937026:A:AC	donor_gain	1.0000
9:3937027:C:CC	donor_gain	1.0000
9:3937027:CG:C	donor_gain	1.0000
9:3937190:C:CC	acceptor_gain	1.0000
9:4118895:C:CT	acceptor_gain	1.0000
9:4118896:A:T	acceptor_gain	1.0000
9:3830693:TTGG:T	donor_gain	0.9900
9:3856003:GCTT:G	donor_loss	0.9900
9:3856006:TA:T	donor_loss	0.9900
9:3856007:A:AC	donor_gain	0.9900
9:3856007:A:C	donor_loss	0.9900
9:3856008:C:CC	donor_gain	0.9900
9:3856182:AACC:A	acceptor_loss	0.9900
9:3856185:CT:C	acceptor_loss	0.9900
9:3856186:T:C	acceptor_loss	0.9900
9:3879591:GGGAG:G	acceptor_gain	0.9900
9:3879596:C:CC	acceptor_gain	0.9900
9:3898685:CTTTA:C	donor_loss	0.9900
9:3898686:TTTA:T	donor_loss	0.9900
9:3898687:TTA:T	donor_loss	0.9900

AlphaMissense

6048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:3932458:A:G	C474R	1.000
9:3937049:G:C	H462Q	1.000
9:3937049:G:T	H462Q	1.000
9:3937051:G:C	H462D	1.000
9:3937076:G:C	F453L	1.000
9:3937076:G:T	F453L	1.000
9:3937077:A:G	F453S	1.000
9:3937078:A:G	F453L	1.000
9:3937105:A:G	C444R	1.000
9:3937141:G:C	H432D	1.000
9:3937149:A:G	L429P	1.000
9:3937166:A:C	F423L	1.000
9:3937166:A:T	F423L	1.000
9:3937168:A:G	F423L	1.000
9:4117809:G:C	H402D	1.000
9:4117817:A:G	L399P	1.000
9:4117834:G:C	F393L	1.000
9:4117834:G:T	F393L	1.000
9:4117836:A:G	F393L	1.000
9:3932402:A:C	H492Q	0.999
9:3932402:A:T	H492Q	0.999
9:3932404:G:C	H492D	0.999
9:3932412:A:G	L489P	0.999
9:3932424:T:C	D485G	0.999
9:3932431:A:C	Y483D	0.999
9:3932441:A:C	C479W	0.999
9:3932442:C:G	C479S	0.999
9:3932443:A:G	C479R	0.999
9:3932443:A:T	C479S	0.999
9:3932456:A:C	C474W	0.999

dbSNP variants (sampled 300 via entrez): RS1000000061 (9:3925624 C>T), RS1000000567 (9:4316540 C>G), RS1000001697 (9:4110975 A>C,G), RS1000001714 (9:4024030 A>C), RS1000002410 (9:3953597 T>C), RS1000003175 (9:4473244 G>C), RS1000004601 (9:3897224 G>A), RS1000004729 (9:4305536 C>G), RS1000007543 (9:4415090 A>G), RS1000012220 (9:4083664 A>C), RS1000012939 (9:4293805 T>C), RS1000012966 (9:4087635 T>G), RS1000013372 (9:4227471 G>A), RS1000013650 (9:3992836 T>A,C), RS1000019964 (9:4212061 G>A,T)

Disease associations

OMIM: gene MIM:610192 | disease phenotypes: MIM:610199

GenCC curated gene-disease

Disease	Classification	Inheritance
neonatal diabetes mellitus with congenital hypothyroidism	Definitive	Autosomal recessive
Tourette syndrome	Limited	Unknown

Mondo (7): neonatal diabetes mellitus with congenital hypothyroidism (MONDO:0012436), monogenic diabetes (MONDO:0015967), diabetes mellitus (MONDO:0005015), transient neonatal diabetes mellitus (MONDO:0020525), aniridia (MONDO:0019172), congenital hypothyroidism (MONDO:0018612), Tourette syndrome (MONDO:0007661)

Orphanet (4): Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome (Orphanet:79118), Rare genetic diabetes mellitus (Orphanet:183625), Congenital hypothyroidism (Orphanet:442), OBSOLETE: Aniridia (Orphanet:77)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000219	Thin upper lip vermilion
HP:0000260	Wide anterior fontanel
HP:0000286	Epicanthus
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000453	Choanal atresia
HP:0000557	Buphthalmos
HP:0000819	Diabetes mellitus
HP:0000851	Congenital hypothyroidism
HP:0000938	Osteopenia
HP:0001087	Developmental glaucoma
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001409	Portal hypertension
HP:0001511	Intrauterine growth retardation
HP:0001537	Umbilical hernia
HP:0001737	Pancreatic cysts
HP:0001744	Splenomegaly
HP:0002036	Hiatus hernia
HP:0002240	Hepatomegaly
HP:0002594	Pancreatic hypoplasia
HP:0002719	Recurrent infections
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration
HP:0002944	Thoracolumbar scoliosis

GWAS associations

92 associations (top):

Study	Trait	p-value
GCST000244_5	Type 1 diabetes	3.000000e-06
GCST000392_36	Type 1 diabetes	5.000000e-12
GCST000523_2	Methotrexate pharmacokinetics (acute lymphoblastic leukemia)	3.000000e-07
GCST000568_13	Fasting blood glucose	1.000000e-12
GCST001351_5	Type 2 diabetes	2.000000e-14
GCST001527_32	Fasting blood glucose (BMI interaction)	7.000000e-07
GCST001666_3	Type 2 diabetes	6.000000e-12
GCST001856_15	Thyroid hormone levels	3.000000e-08
GCST001856_38	Thyroid hormone levels	1.000000e-06
GCST001951_4	Alzheimer’s disease biomarkers	1.000000e-08
GCST001951_5	Alzheimer’s disease biomarkers	3.000000e-09
GCST002352_34	Type 2 diabetes	5.000000e-06
GCST002365_12	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 2 peripheral neuropathy)	4.000000e-06
GCST002586_11	Fasting plasma glucose	4.000000e-09
GCST002752_2	Spontaneous preterm birth (preterm delivery)	7.000000e-06
GCST003391_4	Low high density lipoprotein cholesterol levels	7.000000e-06
GCST003400_43	Type 2 diabetes	6.000000e-08
GCST003467_4	Glaucoma (primary angle closure)	1.000000e-14
GCST003467_5	Glaucoma (primary angle closure)	1.000000e-11
GCST003989_14	Chin dimples	6.000000e-19
GCST004070_12	Cerebrospinal P-tau181p levels	3.000000e-08
GCST004071_4	Cerebrospinal T-tau levels	1.000000e-06
GCST004183_4	Lung function (FEV1)	2.000000e-10
GCST004294_12	Nicotine dependence	1.000000e-06
GCST004601_111	Red blood cell count	9.000000e-12
GCST004604_131	Hematocrit	1.000000e-12
GCST004615_60	Hemoglobin concentration	4.000000e-11
GCST004750_27	Squamous cell lung carcinoma	6.000000e-06
GCST004766_11	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	3.000000e-07
GCST004894_146	Type 2 diabetes	3.000000e-08

EFO canonical traits (40, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004730	hormone measurement
EFO:0004760	t-tau measurement
EFO:0004763	p-tau measurement
EFO:0000180	HIV-1 infection
EFO:0006917	spontaneous preterm birth
EFO:0006922	delivery measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004314	forced expiratory volume
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007681	triglyceride change measurement
EFO:0004695	intraocular pressure measurement
EFO:0004469	HOMA-B
EFO:0005213	central corneal thickness
EFO:0004468	glucose measurement
EFO:0006335	systolic blood pressure
EFO:0007660	neuroticism measurement
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004713	FEV/FVC ratio
EFO:0009941	Inhalant adrenergic use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0010103	response to peginterferon alfa-2a
EFO:0009766	asparagine measurement
EFO:0005000	leptin measurement
EFO:0004346	neuroimaging measurement
EFO:0011013	vaginal microbiome measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D015783	Aniridia	C11.250.060; C11.270.060; C11.941.375.060; C16.131.384.079; C16.320.290.078
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850
C565705	Diabetes Mellitus, Neonatal, with Congenital Hypothyroidism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression, affects cotreatment, decreases expression	8
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	decreases expression, affects cotreatment	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases methylation, decreases methylation, affects cotreatment	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00121355	PHASE4	COMPLETED	Novofine Autocover Safety Needle Versus BD Safety Glide
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00162344	PHASE4	COMPLETED	A Study of Stress Heart Imaging in Patients With Diabetes at Risk for Coronary Disease.
NCT00177138	PHASE4	TERMINATED	Use of Campath for Induction and Maintenance Therapy in Pancreas After Kidney Transplantation
NCT00182494	PHASE4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00202618	PHASE4	UNKNOWN	Rationale and Design for Shiga Microalbuminuria Reduction Trial
NCT00209170	PHASE4	COMPLETED	Depression-Diabetes Mechanisms: Urban African Americans
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00212004	PHASE4	TERMINATED	Pioglitazone Protects Diabetes Mellitus (DM) Patients Against Re-Infarction (PPAR Study)
NCT00219440	PHASE4	COMPLETED	A Portion-controlled Diet Will Prevent Weight Gain in Diabetics Treated With ACTOS
NCT00225849	PHASE4	UNKNOWN	Japanese Primary Prevention Project With Aspirin
NCT00231894	PHASE4	COMPLETED	Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00235014	PHASE4	COMPLETED	A Study for Prevention of Kidney Disease in Diabetic Patients (BENEDICT)
NCT00236379	PHASE4	COMPLETED	A Study of the Effects of Risperidone and Olanzapine on Blood Glucose (Sugar) in Patients With Schizophrenia or Schizoaffective Disorder
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00264901	PHASE4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00274274	PHASE4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00282451	PHASE4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes