CUL3

cullin 3, the group of Cullins

Basic information

Region (hg38): 2:224470149-224585397

Links

ENSG00000036257 ∙ NCBI:8452 ∙ OMIM:603136 ∙ HGNC:2553 ∙ Uniprot:Q13618 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pseudohypoaldosteronism type 2E (Strong), mode of inheritance: AD
• pseudohypoaldosteronism type 2E (Supportive), mode of inheritance: AD
• pseudohypoaldosteronism type 2E (Strong), mode of inheritance: AD
• neurodevelopmental disorder with or without autism or seizures (Strong), mode of inheritance: AD
• pseudohypoaldosteronism type 2E (Definitive), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism, type IIE	AD	Renal	Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective	Neurologic; Renal	22266938; 31696658; 31780330; 32341456; 33097317

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CUL3 gene.

• not provided (214 variants)
• Pseudohypoaldosteronism type 2E (114 variants)
• Autosomal dominant pseudohypoaldosteronism type 1 (73 variants)
• Neurodevelopmental disorder with or without autism or seizures (16 variants)
• Inborn genetic diseases (12 variants)
• CUL3-related condition (8 variants)
• Neurodevelopmental disorder with or without autism or seizures;Pseudohypoaldosteronism type 2E (5 variants)
• not specified (4 variants)
• Pseudohypoaldosteronism type 2E;Neurodevelopmental disorder with or without autism or seizures (4 variants)
• Autism spectrum disorder (2 variants)
• Intellectual disability (2 variants)
• Abnormal cardiovascular system morphology (1 variants)
• CUL3-Related Disorders (1 variants)
• Complex neurodevelopmental disorder (1 variants)
• Neurodevelopmental disorder (1 variants)
• Neurodevelopmental delay (1 variants)
• Pseudohypoaldosteronism type 2A (1 variants)
• NEURODEVELOPMENTAL DISORDER WITHOUT AUTISM OR SEIZURES (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CUL3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	35	3	41
missense	1	5	62	4	1	73
nonsense	7	2	3			12
start loss			1			1
frameshift	12	10	6			28
inframe indel			4			4
splice donor/acceptor (+/-2bp)	2	4	1			7
splice region		1	10	4	1	16
non coding			60	34	55	149
Total	22	21	140	73	59

Variants in CUL3

This is a list of pathogenic ClinVar variants found in the CUL3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-224470157-A-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470254-T-C		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign (Jan 13, 2018)
2-224470272-A-T		Pseudohypoaldosteronism type 2E	Benign (Jan 13, 2018)
2-224470287-G-A		Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470323-T-C		Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470435-G-A		Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470456-G-A		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign (Jan 13, 2018)
2-224470459-G-GT		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jun 14, 2016)
2-224470479-C-T		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470492-A-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-224470508-TA-T		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jun 14, 2016)
2-224470573-A-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign (Jan 12, 2018)
2-224470580-A-T		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-224470649-T-C		Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 12, 2018)
2-224470712-CCT-C		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
2-224470782-A-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign/Likely benign (Jan 13, 2018)
2-224470853-T-C		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224470878-A-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign (Jan 13, 2018)
2-224471089-T-C		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign/Likely benign (Jan 12, 2018)
2-224471097-T-C		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign (Jan 13, 2018)
2-224471111-T-A		Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 13, 2018)
2-224471149-C-G		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jun 14, 2016)
2-224471219-C-T		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Uncertain significance (Jan 12, 2018)
2-224471295-ACAGG-A		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jun 14, 2016)
2-224471300-C-G		Autosomal dominant pseudohypoaldosteronism type 1 • Pseudohypoaldosteronism type 2E	Benign/Likely benign (Oct 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CUL3	protein_coding	protein_coding	ENST00000264414	16	115244

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000398	125719	0	8	125727	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.75	145	419	0.346	0.0000222	5098
Missense in Polyphen		37	160.33	0.23077		2018
Synonymous	-1.10	155	139	1.12	0.00000720	1382
Loss of Function	5.28	4	40.1	0.0997	0.00000218	504

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.000207	0.000198
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.000109	0.000109
South Asian	0.0000331	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Core component of multiple cullin-RING-based BCR (BTB- CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin- protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, H2AFY and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3- RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27716508). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4 (PubMed:23387299, PubMed:23453970, PubMed:23576762). The BCR(KLHL20) E3 ubiquitin ligase complex is involved in interferon response and anterograde Golgi to endosome transport: it mediates both ubiquitination leading to degradation and 'Lys-33'-linked ubiquitination (PubMed:20389280, PubMed:21840486, PubMed:21670212, PubMed:24768539). The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB (PubMed:19995937). The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation (PubMed:23455478). The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway (PubMed:29769719). The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) (PubMed:22578813). The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832). Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and RBX1, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. The BCR(KCTD17) E3 ubiquitin ligase complex mediates ubiquitination and degradation of TCHP, a down-regulator of cilium assembly, thereby inducing ciliogenesis (PubMed:25270598). The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity (PubMed:27798626). {ECO:0000269|PubMed:10500095, ECO:0000269|PubMed:11311237, ECO:0000269|PubMed:15897469, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:16524876, ECO:0000269|PubMed:17543862, ECO:0000269|PubMed:18397884, ECO:0000269|PubMed:19261606, ECO:0000269|PubMed:19995937, ECO:0000269|PubMed:20389280, ECO:0000269|PubMed:21670212, ECO:0000269|PubMed:21840486, ECO:0000269|PubMed:22085717, ECO:0000269|PubMed:22358839, ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:22632832, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23455478, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:24768539, ECO:0000269|PubMed:25270598, ECO:0000269|PubMed:26399832, ECO:0000269|PubMed:27565346, ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:29769719}.
• Disease: DISEASE: Pseudohypoaldosteronism 2E (PHA2E) [MIM:614496]: An autosomal dominant disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. {ECO:0000269|PubMed:22266938}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Ncore;Hereditary Leiomyomatosis and Renal Cell Carcinoma Pathway;Hedgehog Signaling Pathway;Signaling by WNT;Signal Transduction;Post-translational protein modification;Metabolism of proteins;Immune System;Regulation of RAS by GAPs;Adaptive Immune System;ATF-2 transcription factor network;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;Hedgehog ,on, state;Signaling by Hedgehog;Neddylation;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Degradation of DVL;Aurora B signaling;TCF dependent signaling in response to WNT;Canonical Wnt signaling pathway (Consensus)

Recessive Scores

• pRec: 0.186

Intolerance Scores

• loftool: 0.416
• rvis_EVS: -0.14
• rvis_percentile_EVS: 43.29

Haploinsufficiency Scores

• pHI: 0.252
• hipred: Y
• hipred_score: 0.745
• ghis: 0.548

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cul3
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; embryo phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;negative regulation of transcription by RNA polymerase II;MAPK cascade;protein polyubiquitination;trophectodermal cellular morphogenesis;ubiquitin-dependent protein catabolic process;protein monoubiquitination;endoplasmic reticulum to Golgi vesicle-mediated transport;cell cycle arrest;mitotic metaphase plate congression;integrin-mediated signaling pathway;gastrulation;positive regulation of cell population proliferation;Wnt signaling pathway;cell migration;protein ubiquitination;stem cell division;cell projection organization;anaphase-promoting complex-dependent catabolic process;SCF-dependent proteasomal ubiquitin-dependent protein catabolic process;positive regulation of protein ubiquitination;protein destabilization;positive regulation of cytokinesis;negative regulation of Rho protein signal transduction;embryonic cleavage;stress fiber assembly;proteasome-mediated ubiquitin-dependent protein catabolic process;post-translational protein modification;fibroblast apoptotic process;positive regulation of mitotic metaphase/anaphase transition;COPII vesicle coating;nuclear protein quality control by the ubiquitin-proteasome system;liver morphogenesis;negative regulation of canonical Wnt signaling pathway;intrinsic apoptotic signaling pathway
• Cellular component: Golgi membrane;nucleoplasm;cytoplasm;polar microtubule;cytosol;membrane;SCF ubiquitin ligase complex;cullin-RING ubiquitin ligase complex;Cul3-RING ubiquitin ligase complex;sperm flagellum;extracellular exosome
• Molecular function: ubiquitin-protein transferase activity;Notch binding;protein binding;cyclin binding;POZ domain binding;ubiquitin protein ligase binding;protein homodimerization activity;protein heterodimerization activity;ubiquitin protein ligase activity