SIAH1

Summary

SIAH1 (siah E3 ubiquitin protein ligase 1, HGNC:10857) is a protein-coding gene on chromosome 16q12.1, encoding E3 ubiquitin-protein ligase SIAH1 (Q8IUQ4). E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in the development of certain forms of Parkinson’s disease, the regulation of the cellular response to hypoxia and induction of apoptosis. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.

Source: NCBI Gene 6477 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Buratti-Harel syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 13 total — 2 pathogenic
• Phenotypes (HPO): 31
• MANE Select transcript: NM_003031

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10857
Approved symbol	SIAH1
Name	siah E3 ubiquitin protein ligase 1
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	hSIAH1
Ensembl gene	ENSG00000196470
Ensembl biotype	protein_coding
OMIM	602212
Entrez	6477

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000356721, ENST00000380006, ENST00000394725, ENST00000563745, ENST00000565620, ENST00000567973, ENST00000568007, ENST00000573005, ENST00000893204, ENST00000893205, ENST00000893206, ENST00000893207, ENST00000939086

RefSeq mRNA: 2 — MANE Select: NM_003031 NM_001006610, NM_003031

CCDS: CCDS10735, CCDS32444

Canonical transcript exons

ENST00000394725 — 2 exons

Exon	Start	End
ENSE00001654032	48385204	48385413
ENSE00003460222	48360531	48362430

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3769 / max 223.1221, expressed in 1792 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157258	6.4295	1735
157259	4.8643	1629
157260	2.0954	1296
157257	1.9739	578
157263	0.0138	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.23	gold quality
oocyte	CL:0000023	96.42	gold quality
cortical plate	UBERON:0005343	95.75	gold quality
endothelial cell	CL:0000115	95.40	gold quality
ganglionic eminence	UBERON:0004023	95.34	gold quality
esophagus squamous epithelium	UBERON:0006920	95.25	gold quality
amniotic fluid	UBERON:0000173	94.32	gold quality
skin of hip	UBERON:0001554	94.20	gold quality
placenta	UBERON:0001987	94.02	gold quality
germinal epithelium of ovary	UBERON:0001304	93.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.56	gold quality
pigmented layer of retina	UBERON:0001782	93.37	gold quality
upper leg skin	UBERON:0004262	92.85	gold quality
parietal pleura	UBERON:0002400	92.79	gold quality
epithelium of esophagus	UBERON:0001976	92.65	gold quality
epithelium of nasopharynx	UBERON:0001951	92.62	gold quality
squamous epithelium	UBERON:0006914	92.50	gold quality
visceral pleura	UBERON:0002401	92.41	gold quality
ventricular zone	UBERON:0003053	92.33	gold quality
pleura	UBERON:0000977	92.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.87	gold quality
choroid plexus epithelium	UBERON:0003911	91.70	gold quality
embryo	UBERON:0000922	91.44	gold quality
caput epididymis	UBERON:0004358	91.41	gold quality
cauda epididymis	UBERON:0004360	91.27	gold quality
thoracic mammary gland	UBERON:0005200	91.12	gold quality
epithelium of mammary gland	UBERON:0003244	91.08	gold quality
mammary gland	UBERON:0001911	91.06	gold quality
buccal mucosa cell	CL:0002336	90.96	gold quality
corpus epididymis	UBERON:0004359	90.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	19.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, EHMT2, HNF4A, TP53

miRNA regulators (miRDB)

143 targeting SIAH1, 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-8485	100.00	77.57	4731
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 40)

• Siah proteins function as E3 ubiquitin-protein ligases (PMID:11786535)
• The Siah-1 gene promoter was cloned and the basic structure of the Siah-1 gene was determined. (PMID:11852084)
• genetic regulation in tumor reversion (PMID:12399545)
• structural analysis and interaction with Siah-interacting protein (PMID:12421809)
• SIAH1 has been identified as a putative tumor suppressor gene for human hepatocellular carcinomas, with a correlation between its suppressed expression and tumor size and differentiation. (PMID:12557228)
• PEG10 protein associated with SIAH1, a mediator of apoptosis, and overexpression of PEG10 decreased the cell death mediated by SIAH1. (PMID:12810624)
• Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release (PMID:14506261)
• A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site. (PMID:14985507)
• SIAH-mediated down regulation of alternative splicing may be an important developmental difference between otherwise highly conserved T-STAR proteins. (PMID:15163637)
• role of interaction with AF4 and AF4.MLL fusion protein in t(4,11) pathobiology (PMID:15221006)
• polycystin-1 is regulated by Siah-1 through the ubiquitin-dependent proteasome pathway. (PMID:15284290)
• Siah-1L represents a new member of the human Siah family that is induced in response to p53 and plays an important role in the regulation of beta-catenin activity in tumor cells (PMID:15326481)
• inactivating mutations of the Siah-1 may contribute to the development of gastric cancer through beta-catenin stabilization and apoptosis block (PMID:15467739)
• Data show a signalling pathway in which nitric oxide generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1, nuclear translocation and apoptosis. (PMID:15951807)
• SIP engages Siah1 by means of two elements, both of which are required for mediating beta-catenin destruction in cells (PMID:16085652)
• GSK3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH (PMID:16174773)
• analysis of the substrate binding site of Siah ubiquitin ligase (PMID:16615911)
• genetic alterations of SIAH-1 do not significantly contribute to the pathogenesis of Parkinson disease (PMID:16752048)
• HSiah1 lacks the self-regulatory catalytic activity displayed by the ring finger domain of hSiah2 in HEK293 cells. (PMID:16899216)
• Siah-1S (splice variant S) displays a promotion effect on cells tumorigenicity (PMID:17420721)
• Siah-1-mediated alpha-synuclein ubiquitination may play a critical role in Lewy body formation and Parkinson disease pathogenesis (PMID:18065497)
• monoubiquitylation by SIAH1 and SIAH2 represents a possible trigger event for alpha-synuclein aggregation and Lewy body formation (PMID:18070888)
• SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer. (PMID:18089810)
• SIAH1-induced degradation of TRB3 represents a potential regulatory mechanism for TGF-beta signaling. (PMID:18276110)
• SIAH-1 inhibition may represent a new therapeutic strategy in the treatment of human hepatocellular carcinoma. (PMID:18314624)
• Results describe the control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. (PMID:18536714)
• Siah1 (human) and Siah1A (mouse) reduced PHD3 protein levels similar to that observed with Siah2. (PMID:18850011)
• synphilin-1A has a novel role as a regulator of SIAH activity, modulating alpha-synuclein, and formation of Lewy body-like inclusions (PMID:19224863)
• Data show that two mitotic kinases, Aurora-A and Aurora-B, phosphorylate endogenous EB3 at Ser-176, and the phosphorylation triggers disruption of the EB3-SIAH-1 complex, resulting in EB3 stabilization during mitosis. (PMID:19696028)
• JNK and ERK signaling pathways may play an important role in the SIAH1-dependent biological behavior of breast cancer. (PMID:19775288)
• siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller (PMID:19940145)
• increase of the function of SIAH1 to upregulate the expression of Bim may play an important role in the progression of breast cancer (PMID:20082325)
• Immunofluorescence microscopy shows that the intracellular distribution of SIAH-1 and Kid/KIF22 appears to be modified in human tumor tissues compared to normal controls (PMID:20144232)
• Direct ubiquitination of beta-catenin by Siah-1 and regulation by the exchange factor TBL1. (PMID:20181957)
• Siah1 is a bona fide E2F1 target gene, which at least partly, mediates the suppression of beta-catenin/TCF signalling pathway (PMID:20187294)
• these results propose a novel role of SIAH-1 in regulating the expression level of HPH2 through the ubiquitin-proteasome pathway. (PMID:20471960)
• Herp temporarily bound to E3 ligase SIAH1a during proteolytic stress but not during ER stress. (PMID:20604806)
• Overexpression of Siah1L and Siah1 is associated with radiosensitivity of breast cancer. (PMID:20682032)
• ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP. (PMID:21185211)
• results suggest that hypoxia downregulates beta-catenin by increasing Siah-1 expression in a p53-dependent manner (PMID:21466614)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	siah1	ENSDARG00000030871
mus_musculus	Siah1a	ENSMUSG00000036840
mus_musculus	Siah1b	ENSMUSG00000040749
rattus_norvegicus	Siah1	ENSRNOG00000015143
caenorhabditis_elegans		WBGENE00021369

Paralogs (3): SIAH2 (ENSG00000181788), ZSWIM9 (ENSG00000185453), SIAH3 (ENSG00000215475)

Protein

Protein identifiers

E3 ubiquitin-protein ligase SIAH1 — Q8IUQ4 (reviewed: Q8IUQ4)

Alternative names: RING-type E3 ubiquitin transferase SIAH1, Seven in absentia homolog 1, Siah-1a

All UniProt accessions (2): Q8IUQ4, H3BU09

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP. Confers constitutive instability to HIPK2 through proteasomal degradation. It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF signaling. Has some overlapping function with SIAH2. Induces apoptosis in cooperation with PEG3. Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus. GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins. Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4. Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1.

Subunit / interactions. Homodimer. Interacts with group 1 glutamate receptors GRM1 and GRM5. Interacts with DAB1, which may inhibit its activity. Interacts with UBE2E2. Interacts with PEG3. Interacts with GAPDH; leading to stabilize SIAH1. Component of some large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with UBE2I. Interacts with alpha-tubulin. Interacts with PEG10, which may inhibit its activity. Interacts with KHDRBS3. Interacts with SNCAIP. Interacts with HIPK2; the interaction is promoted by DAZAP2 and results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2. Interacts with DAZAP2; the interaction is decreased following phosphorylation of DAZAP2 by HIPK2. Interacts with Bassoon/BSN and Piccolo/PLCO; these interactions negatively regulate SIAH1 E3 ligase activity. Interacts with DCC. Interacts with AXIN1; catalyzes AXIN1 ubiquitination and subsequent proteasome-mediated ubiquitin-dependent degradation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed at a low level. Down-regulated in advanced hepatocellular carcinomas.

Post-translational modifications. Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2.

Disease relevance. Buratti-Harel syndrome (BURHAS) [MIM:619314] An autosomal dominant neurodevelopmental disorder characterized by hypotonia apparent in early infancy, global developmental delay, delayed walking, language and speech delay, impaired intellectual development, and dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10.

Domain organisation. The RING-type zinc finger domain is essential for ubiquitin ligase activity. The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.

Induction. May be induced by p53/TP53, suggesting that it may be required to modulate p53/TP53 response. The relevance of such activity in vivo is however unclear and may not exist.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the SINA (Seven in absentia) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IUQ4-1	1	yes
Q8IUQ4-2	2
Q8IUQ4-3	3, Siah-1S

RefSeq proteins (2): NP_001006611, NP_003022* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR004162	SINA-like_animal	Family
IPR008974	TRAF-like	Homologous_superfamily
IPR013010	Znf_SIAH	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018121	7-in-absentia-prot_TRAF-dom	Domain
IPR049548	Sina-like_RING	Domain

Pfam: PF03145, PF21361, PF21362

UniProt features (82 total): mutagenesis site 30, strand 13, helix 10, binding site 8, sequence variant 5, turn 4, splice variant 3, zinc finger region 2, region of interest 2, sequence conflict 2, chain 1, modified residue 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4CA1	X-RAY DIFFRACTION	1.58
9G0L	X-RAY DIFFRACTION	1.9
4C9Z	X-RAY DIFFRACTION	1.95
5WZZ	X-RAY DIFFRACTION	2.1
2A25	X-RAY DIFFRACTION	2.2
4X3G	X-RAY DIFFRACTION	2.34
4I7D	X-RAY DIFFRACTION	2.4
8HEO	X-RAY DIFFRACTION	2.53
4I7C	X-RAY DIFFRACTION	2.8
4I7B	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUQ4-F1	89.74	0.82

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 (8): 128; 135; 147; 152; 98; 105; 117; 121

Post-translational modifications (1): 19

Mutagenesis-validated functional residues (30):

Position	Phenotype
19	impaired atm mediated phosphorylation, but normal interaction with hipk2 and hipk2 subsequent proteasomal degradation.
19	reduced interaction with hipk2 and hipk2 subsequent proteasomal degradation.
40	loss of function.
41	loss of function; when associated with s-44.
44	loss of function.
55	loss of function; when associated with a-59 and s-72.
55	loss of function; when associated with y-59.
59	loss of function; when associated with a-55 and s-72.
59	loss of function.
66	decreased activity; when associated with t-68.
68	decreased activity; when associated with l-66.
72	loss of function; when associated with a-55 and a-59.
76	decreased activity.
124	in d; does not impair its ability to interact with cacybp and degrade ctnnb1 and pml; when associated with a-214; a-215;
142	in e; does not impair its ability to interact with cacybp and degrade ctnnb1; when associated with a-151.
151	in e; does not impair its ability to interact with cacybp and degrade ctnnb1; when associated with a-142.
152	abolishes ability to degrade dcc.
161–162	in a; does not impair its ability to degrade pml while it abolishes its ability to interact with cacybp and degrade ctnn
198–200	impairs ctnnb1 degradation.
202	no effect.
211	abolishes ability to degrade dcc.
214–215	in d; does not impair its ability to interact with cacybp and degrade ctnnb1 and pml; when associated with a-124; a-231
224	in c; does not impair its ability to interact with cacybp and degrade ctnnb1; when associated with a-233.
226	in a; does not impair its ability to degrade pml while it abolishes its ability to interact with cacybp and degrade ctnn
231–232	in d; does not impair its ability to interact with cacybp and degrade ctnnb1 and pml; when associated with a-124; a-214

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-977225	Amyloid fiber formation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 391 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, WWTAAGGC_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_NEUROGENESIS, WONG_PROTEASOME_GENE_MODULE, GOBP_MALE_GAMETE_GENERATION

GO Biological Process (18): ubiquitin-dependent protein catabolic process (GO:0006511), apoptotic process (GO:0006915), spermatogenesis (GO:0007283), nervous system development (GO:0007399), axon guidance (GO:0007411), anatomical structure morphogenesis (GO:0009653), protein ubiquitination (GO:0016567), protein catabolic process (GO:0030163), protein destabilization (GO:0031648), positive regulation of apoptotic process (GO:0043065), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), neuron apoptotic process (GO:0051402), canonical Wnt signaling pathway (GO:0060070), amyloid fibril formation (GO:1990000), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), multicellular organism development (GO:0007275), cell differentiation (GO:0030154), regulation of apoptotic signaling pathway (GO:2001233)

GO Molecular Function (8): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin conjugating enzyme binding (GO:0031624), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), beta-catenin destruction complex (GO:0030877)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Axon guidance	1
Metabolism of proteins	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Nervous system development	1
Developmental Biology	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic signaling pathway	2
anatomical structure development	2
protein metabolic process	2
apoptotic process	2
regulation of apoptotic process	2
cellular anatomical structure	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
programmed cell death	1
execution phase of apoptosis	1
developmental process involved in reproduction	1
male gamete generation	1
system development	1
axonogenesis	1
neuron projection guidance	1
developmental process	1
protein modification by small protein conjugation	1
macromolecule catabolic process	1
regulation of protein stability	1
positive regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
Wnt signaling pathway	1
supramolecular fiber organization	1
intrinsic apoptotic signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
multicellular organismal process	1
cellular developmental process	1
regulation of signal transduction	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-like protein conjugating enzyme binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIAH1	CACYBP	Q9HB71	997
SIAH1	GAPDH	P00354	990
SIAH1	SKP1	P34991	951
SIAH1	EGLN3	Q9H6Z9	873
SIAH1	SNCAIP	Q9Y6H5	873
SIAH1	EGLN2	Q96KS0	873
SIAH1	UBE2L6	O14933	805
SIAH1	S100A6	P06703	778
SIAH1	FBXO45	P0C2W1	748
SIAH1	HIPK2	Q9H2X6	742
SIAH1	UBE2E2	Q96LR5	651
SIAH1	HIF1A	Q16665	644
SIAH1	CTNNB1	P35222	643
SIAH1	RBX1	P62877	617
SIAH1	EGLN1	Q9GZT9	610

IntAct

343 interactions, top by confidence:

A	B	Type	Score
PHC2	SIAH1	psi-mi:“MI:0915”(physical association)	0.740
SIAH1	PUF60	psi-mi:“MI:0915”(physical association)	0.740
PUF60	SIAH1	psi-mi:“MI:0915”(physical association)	0.740
UBE2K	SIAH1	psi-mi:“MI:0915”(physical association)	0.670
SIAH1	EEF1D	psi-mi:“MI:0915”(physical association)	0.670
SIAH1	SIAH1	psi-mi:“MI:0915”(physical association)	0.670
SIAH1	UBE2K	psi-mi:“MI:0915”(physical association)	0.670
ZBP1	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	PRPF31	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	SDCBP	psi-mi:“MI:0915”(physical association)	0.560
DNALI1	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	SYT7	psi-mi:“MI:0915”(physical association)	0.560
KIF1B	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	MAPKBP1	psi-mi:“MI:0915”(physical association)	0.560
UPP2	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	INHA	psi-mi:“MI:0915”(physical association)	0.560
PFKM	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
PYGB	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	MX1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	AQP1	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	CAPG	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	BCL6	psi-mi:“MI:0915”(physical association)	0.560
CDC34	SIAH1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (452): UBE2D1 (Reconstituted Complex), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid), SIAH1 (Two-hybrid)

ESM2 similar proteins: A8X679, M9MRI4, O08722, O43255, P0DTL6, P0DW87, P0DW89, P0DW91, P21461, P29304, P61092, P61093, P93748, Q06985, Q06986, Q08CH8, Q10L91, Q2TAD9, Q3MV19, Q4U5R4, Q505D9, Q6GNX1, Q6IWL4, Q6J1I8, Q6J212, Q6J2U6, Q6ZTA4, Q7SYL3, Q7ZVG6, Q84JL3, Q86MW9, Q8C7M3, Q8I147, Q8IUQ4, Q8IW03, Q8K1S3, Q8K2J9, Q8R4T2, Q8S3N1, Q8T3Y0

Diamond homologs: A8X679, O43255, P21461, P29304, P61092, P61093, P93748, Q06985, Q06986, Q10L91, Q7SYL3, Q7ZVG6, Q84JL3, Q86MW9, Q8I147, Q8IUQ4, Q8IW03, Q8R4T2, Q8T3Y0, Q920M9, Q965X6, Q9FKD9, Q9I8X5, Q9M2P4, Q9STN8, Q84K34, Q8S3N1, Q9C6H2, Q9C6H4, Q9C9M0, Q9FKD5, Q9FKD6, Q9FKD7, Q9C6H3, P0DTL6, P0DW91, Q7XA77, Q93WE4, Q9FM14, P0DW87

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
SIAH1	down-regulates	NUMB	ubiquitination
TP53	“up-regulates quantity by expression”	SIAH1	“transcriptional regulation”
SIAH1	down-regulates	SNCAIP	ubiquitination
SIAH1	up-regulates	NOTCH1	relocalization
ATM	down-regulates	SIAH1	phosphorylation
SIAH1	up-regulates	NOTCH	relocalization
Ub:E2	“up-regulates activity”	SIAH1	ubiquitination
SIAH1	“form complex”	SCF(TBL1)	binding
SIAH1	“down-regulates quantity by destabilization”	JADE1	polyubiquitination
PKD1	“up-regulates activity”	SIAH1	binding
SIAH1	“down-regulates quantity by destabilization”	HIPK2	polyubiquitination
ATR	“down-regulates activity”	SIAH1	phosphorylation
SIAH1	“down-regulates quantity”	HIPK2	ubiquitination
SIAH1	“down-regulates quantity by destabilization”	YBX1	ubiquitination
SIAH1	“down-regulates quantity by destabilization”	KHDRBS3	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1082505	NM_003031.4(SIAH1):c.383G>T (p.Cys128Phe)	Pathogenic
1082507	NM_003031.4(SIAH1):c.520G>C (p.Gly174Arg)	Pathogenic

SpliceAI

159 predictions. Top by Δscore:

Variant	Effect	Δscore
16:48362426:CATTT:C	acceptor_gain	0.9900
16:48362428:TTT:T	acceptor_gain	0.9900
16:48362444:A:C	acceptor_gain	0.9900
16:48356608:A:AG	acceptor_gain	0.9800
16:48356609:A:G	acceptor_gain	0.9800
16:48362427:ATTT:A	acceptor_gain	0.9800
16:48362428:TTTC:T	acceptor_loss	0.9800
16:48362429:TT:T	acceptor_gain	0.9800
16:48362430:TC:T	acceptor_loss	0.9800
16:48362431:C:CA	acceptor_loss	0.9800
16:48362431:C:CC	acceptor_gain	0.9800
16:48362432:T:A	acceptor_loss	0.9800
16:48362436:A:AC	acceptor_gain	0.9800
16:48362443:C:CT	acceptor_gain	0.9700
16:48363645:A:AC	donor_gain	0.9700
16:48363646:C:CC	donor_gain	0.9700
16:48362440:A:C	acceptor_gain	0.9600
16:48362440:A:AC	acceptor_gain	0.9300
16:48362444:A:AC	acceptor_gain	0.9100
16:48362595:CA:C	donor_gain	0.9100
16:48362812:A:AC	donor_gain	0.9000
16:48362813:C:CC	donor_gain	0.9000
16:48362436:A:C	acceptor_gain	0.8900
16:48362443:CA:C	acceptor_loss	0.8700
16:48362849:G:C	donor_gain	0.8700
16:48362936:T:TC	acceptor_gain	0.8700
16:48362813:CT:C	donor_gain	0.8600
16:48356612:ATTT:A	acceptor_gain	0.8400
16:48363826:C:A	donor_gain	0.8400
16:48356607:C:G	acceptor_gain	0.8300

AlphaMissense

1859 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:48361593:A:T	I279N	1.000
16:48361605:A:C	I275S	1.000
16:48361605:A:G	I275T	1.000
16:48361605:A:T	I275N	1.000
16:48361611:A:G	L273S	1.000
16:48361628:A:C	F267L	1.000
16:48361628:A:T	F267L	1.000
16:48361629:A:G	F267S	1.000
16:48361630:A:G	F267L	1.000
16:48361630:A:T	F267I	1.000
16:48361653:A:G	F259S	1.000
16:48361659:A:G	L257P	1.000
16:48361659:A:T	L257Q	1.000
16:48361661:A:C	C256W	1.000
16:48361663:A:G	C256R	1.000
16:48361665:T:A	D255V	1.000
16:48361710:G:C	P240R	1.000
16:48361710:G:T	P240H	1.000
16:48361717:C:G	A238P	1.000
16:48361721:C:A	W236C	1.000
16:48361721:C:G	W236C	1.000
16:48361722:C:G	W236S	1.000
16:48361723:A:G	W236R	1.000
16:48361723:A:T	W236R	1.000
16:48361749:A:G	L227P	1.000
16:48361749:A:T	L227Q	1.000
16:48361755:A:G	L225P	1.000
16:48361755:A:T	L225H	1.000
16:48361758:C:G	R224P	1.000
16:48361762:A:C	Y223D	1.000

dbSNP variants (sampled 300 via entrez): RS1000089888 (16:48384762 C>G,T), RS1000113440 (16:48387102 G>A,C), RS1000136155 (16:48386818 C>G), RS1000183978 (16:48377711 GA>G,GAA), RS1000275878 (16:48371795 A>G), RS1000388555 (16:48383042 G>C,T), RS1000403933 (16:48380279 A>G), RS1000548495 (16:48387413 TC>T), RS1000882423 (16:48362720 T>A,C), RS1001073943 (16:48374836 G>A,T), RS1001212157 (16:48385236 C>T), RS1001217024 (16:48360827 A>G), RS1001361877 (16:48360899 C>T), RS1001415365 (16:48372984 G>A,C), RS1001531362 (16:48372832 C>G)

Disease associations

OMIM: gene MIM:602212 | disease phenotypes: MIM:619314

GenCC curated gene-disease

Disease	Classification	Inheritance
Buratti-Harel syndrome	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (2): Buratti-Harel syndrome (MONDO:0859144), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000220	Velopharyngeal insufficiency
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000750	Delayed speech and language development
HP:0001270	Motor delay
HP:0001601	Laryngomalacia
HP:0001631	Atrial septal defect
HP:0001792	Small nail
HP:0002020	Gastroesophageal reflux
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0006532	Recurrent pneumonia
HP:0008551	Microtia
HP:0008947	Floppy infant
HP:0010055	Broad hallux
HP:0011304	Broad thumb
HP:0012520	Dilation of Virchow-Robin spaces

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST008151_21	Waist circumference	7.000000e-06
GCST008160_5	Waist circumference	7.000000e-06
GCST008163_467	Height	4.000000e-07
GCST012490_381	Femur bone mineral density x serum urate levels interaction	4.000000e-08
GCST90002390_86	Mean corpuscular hemoglobin	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
naringenin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
ochratoxin A	decreases expression	1
hydroquinone	increases expression	1
beta-methylcholine	affects expression	1
cyanoginosin LR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one	increases expression	1
Resveratrol	decreases expression	1
Leflunomide	increases expression	1
Glyphosate	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2FB	Abcam HeLa SIAH1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder