HMBS

Summary

HMBS (hydroxymethylbilane synthase, HGNC:4982) is a protein-coding gene on chromosome 11q23.3, encoding Porphobilinogen deaminase (P08397). As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 3145 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acute intermittent porphyria (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 755 total — 132 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000190

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4982
Approved symbol	HMBS
Name	hydroxymethylbilane synthase
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000256269
Ensembl biotype	protein_coding
OMIM	609806
Entrez	3145

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 23 protein_coding, 14 retained_intron, 7 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000392841, ENST00000442944, ENST00000534956, ENST00000535253, ENST00000535793, ENST00000536185, ENST00000536813, ENST00000537841, ENST00000539045, ENST00000542044, ENST00000542345, ENST00000542729, ENST00000542822, ENST00000543090, ENST00000543543, ENST00000543821, ENST00000544182, ENST00000544360, ENST00000544387, ENST00000545621, ENST00000545901, ENST00000546226, ENST00000546302, ENST00000640813, ENST00000648026, ENST00000648374, ENST00000648488, ENST00000649823, ENST00000649868, ENST00000650101, ENST00000650307, ENST00000652429, ENST00000686218, ENST00000686690, ENST00000691144, ENST00000691249, ENST00000877118, ENST00000933407, ENST00000933408, ENST00000933409, ENST00000933410, ENST00000933411, ENST00000933412, ENST00000959927, ENST00000959928, ENST00000959929

RefSeq mRNA: 15 — MANE Select: NM_000190 NM_000190, NM_001024382, NM_001258208, NM_001258209, NM_001425052, NM_001425053, NM_001425054, NM_001425056, NM_001425057, NM_001425058, NM_001425059, NM_001425061, NM_001425062, NM_001425063, NM_001425065

CCDS: CCDS41726, CCDS58186, CCDS58187, CCDS8409

Canonical transcript exons

ENST00000652429 — 14 exons

Exon	Start	End
ENSE00001053977	119093110	119093549
ENSE00003460195	119092404	119092523
ENSE00003471706	119090190	119090265
ENSE00003499774	119084881	119085066
ENSE00003525344	119089990	119090067
ENSE00003527962	119088255	119088308
ENSE00003528094	119092125	119092163
ENSE00003537468	119088635	119088707
ENSE00003609229	119092758	119092811
ENSE00003610664	119092935	119093021
ENSE00003611393	119089683	119089760
ENSE00003646270	119089082	119089131
ENSE00003662430	119089217	119089272
ENSE00003788716	119091413	119091526

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.7182 / max 3151.1845, expressed in 1790 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117086	24.4629	1784
117089	14.0216	111
117088	1.2061	81
117087	0.7560	327
117090	0.2716	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	97.84	gold quality
bone marrow	UBERON:0002371	95.93	gold quality
bone marrow cell	CL:0002092	94.17	gold quality
mucosa of transverse colon	UBERON:0004991	92.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.61	gold quality
apex of heart	UBERON:0002098	90.51	gold quality
gastrocnemius	UBERON:0001388	89.31	gold quality
muscle of leg	UBERON:0001383	88.53	gold quality
right lobe of liver	UBERON:0001114	88.22	gold quality
rectum	UBERON:0001052	87.91	gold quality
islet of Langerhans	UBERON:0000006	87.84	gold quality
right adrenal gland	UBERON:0001233	87.78	gold quality
tendon of biceps brachii	UBERON:0008188	87.72	silver quality
blood	UBERON:0000178	87.48	gold quality
left adrenal gland	UBERON:0001234	87.37	gold quality
left adrenal gland cortex	UBERON:0035825	87.19	gold quality
gingival epithelium	UBERON:0001949	87.06	gold quality
muscle organ	UBERON:0001630	86.93	gold quality
stromal cell of endometrium	CL:0002255	86.92	gold quality
right adrenal gland cortex	UBERON:0035827	86.90	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.88	gold quality
heart left ventricle	UBERON:0002084	86.72	gold quality
monocyte	CL:0000576	86.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.37	gold quality
cardiac ventricle	UBERON:0002082	86.31	gold quality
mononuclear cell	CL:0000842	86.24	gold quality
transverse colon	UBERON:0001157	85.97	gold quality
adrenal cortex	UBERON:0001235	85.96	gold quality
leukocyte	CL:0000738	85.92	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	842.15
E-MTAB-9221	yes	838.35
E-MTAB-10042	yes	712.43
E-HCAD-4	yes	165.69
E-CURD-112	yes	77.98
E-CURD-122	yes	19.37
E-HCAD-9	yes	11.24
E-MTAB-9388	yes	9.40
E-MTAB-9067	yes	7.70
E-HCAD-10	yes	4.21
E-CURD-98	no	1578.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, GATA1, JUN, MYC, NFE2, SP1

miRNA regulators (miRDB)

25 targeting HMBS, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-487A-5P	98.85	69.37	993
HSA-MIR-487B-5P	98.85	69.48	987
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-409-5P	97.31	68.07	364
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-582-3P	96.69	67.38	1019
HSA-MIR-6806-5P	96.37	68.74	587

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene (PMID:11399210)
• In Italy, molecular analysis of the HMBS gene in acute intermittent porphyria patients and in family members of Italian ancestry identified 13 different mutations among 14 patients; 7 are new findings. (PMID:11831862)
• 40% of all mutations identified among the Polish acute intermittent porphyria (AIP)patients in this study are novel, indicating the heterogeneity of molecular defects causing AIP. (PMID:11857754)
• A novel mutation of the PBGD gene has been identified in a patient with acute intermittent porphyria presenting with severe and bilateral axonal radial motor neuropathy. (PMID:11940707)
• A mutation that results in an inactive holo-protein that exists as a complex with two substrate molecules covalently bound to the dipyrromethane cofactor arising from the reaction between the apo-protein and pre-uroporphyrinogen (PMID:12773194)
• Modulation of penetrance by the wild-type allele in dominantly inherited erythrohepatic and acute hepatic porphyrias was studied using HMBS. (PMID:14669009)
• screening of the DNA of 20 unrelated individuals revealed 20 different mutations, 11 of which had not been reported previously; the novel mutations affected intron 1, exon 5, intron 6, intron 7, intron 9, intron 13 , exon 15. (PMID:15003823)
• recurrent mutations G111R and R173Q occur at CpG motifs in the porphobilinogen deaminase gene in acute intermittent porphyria patients (PMID:15669678)
• Three novel mutations within the HMBS gene are associated with acute intermittent porphyria. (PMID:16211556)
• Sequencing of the hydroxymethylbilane synthase and uroporphyrinogen decarboxylase genes confirmed the relatively rare diagnosis of dual porphyria, and revealed a novel uroporphyrinogen decarboxylase mutation (PMID:16390615)
• the R173W mutation may have a role in acute intermittent porphyria (PMID:16817012)
• We demonstrate that the PBGD cellular pool is controlled by the proteasome activity, which in turn is down regulated by hemin or up-regulated by Pb-ALAD. (PMID:16935474)
• the search for mutations identified among Slavic acute intermittent porphyria patients 65 such mutations were found and concluded that there is not a distinct predominance of certain mutations in Slavs (PMID:17298216)
• Identification of a nonsense mutation in the porphobilinogen deaminase gene on chromosome 11q23.3, which harbors the mutations causing acute intermittent porphyria, as the underlying genetic defect in Chester porphyria. (PMID:17298217)
• The motor neuropathy showed a steady and gradual improvement following the hematin treatment. Molecular analysis of the porphobilinogen deaminase gene revealed a short segment deletion. (PMID:17459418)
• Molecular analyses of the PBGD gene revealed a novel mutation in exon 15, the 973insG. (PMID:18070416)
• A mother and two children had a C insertion in exon 14 resulting in acute intermittent porphyria. (PMID:18405488)
• Recombinant T59I and V215M had residual activity of 80.6% and 19.4%, respectively, of that of the wild type enzyme. (PMID:18406650)
• 12-bp deletion mutation resulting in a 4-amino acid (AA) deletion from AA positions 337 to 340 found in patient and two family members (PMID:18554962)
• Molecular analysis of twenty-four unrelated Chinese acute intermittent porphyria patients from Taiwan identified twenty-five HMBS mutations. There were 10 missense (40%), four nonsense (16%), five frame-shift (20%) and six splice site (24%) mutations. (PMID:18627369)
• structure provides insights into the mechanism of action of PBGD at the molecular level and could aid the development of potential drugs for the up-regulation of PBGD activity in acute intermittent porphyria (PMID:18936296)
• The decrease in the expression of ubiquitous HMBS and UROS mRNAs under hypoxia is associated with accumulation of hypoxia-inducible factor 1alpha protein. (PMID:19021769)
• 6 mutations in exons common to housekeeping & erythroid-specific isoforms were evaluated at the structural level based on the 3-D structure of the E. coli enzyme. The new missense c.95G>C(p.R32P) is the 1st de novo mutation in the Israeli AIP population. (PMID:19138865)
• structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 A (PMID:19207107)
• Molecular analyses of the hydroxymethylbilane synthase gene revealed seven mutations, in Acute intermittent porphyria (PMID:19292878)
• The novel mutations of HMBS gene were three missense (R26L, R173G and D178H), two frameshift (c.749_765dup and c.874insC) and one intronic deletion (IVS12+3_+11delAGGGCCTGT). (PMID:19656452)
• The informative SNPs of HMBS gene reveal a distinctive haplotype which segregates with the R116W mutation present in the Dutch AIP families (-64T, 1345 G, 2479 G, 3581 G, 6479 T, 7064 C and 8578 A). (PMID:19656453)
• Molecular genetic study of acute intermittent porphyria in Russia: mutation analysis and functional polymorphism search in porphobilinogen deaminase gene (PMID:20536026)
• We identified a monoallelic missense mutation p.Arg201Gly (c.601CNG)in HMBS gene in the patient with Lichen sclerosus et atrophicus-like skin lesions. (PMID:20580577)
• Dense geographic aggregation with one identical haplotype strongly suggests a remote founder phenomenon for these Venezuelan acute intermittent porphyria families, carrying an unreported but most frequent HMBS mutation. (PMID:20978940)
• Two novel porphobilinogen deaminase mutations have been identified in acute intermittent porphyria patients with accompanying anemia in mainland China. (PMID:21669542)
• One small deletion and six nucleotide substitutions within the 5’UTR and the housekeeping promoter of HMBS gene are found responsible for the non-erythroid form of acute intermittent porphyria. (PMID:22748422)
• Findings indicate that using TATA-binding protein (TBP) alone or in combination with hydroxymethylbilane synthase (HMBS) as endogenous controls could be a reliable method for normalizing qRT-PCR data in hepatoma cell lines treated with TNF-alpha. (PMID:23811755)
• Conformational stability and activity of hydroxymethylbilane synthase (HMSB) and the acute intermittent porphyria K132N and V215E HMSB mutations. (PMID:23815679)
• Letter/Case Report: R173W mutation of HMBS gene can cause rhabdomyolysis in patients with variant acute intermittent porphyria. (PMID:25389600)
• in the hepatic cancer tissue of two acute porphyria patients, somatic second-hit mutations result in nearly complete inactivation of PPOX and HMBS (PMID:25445397)
• study of hydroxymethylbilane synthase mutations and polymorphisms in Brazilian families with acute intermittent porphyria (PMID:25703257)
• we report a novel PBGD missense mutation. (PMID:25870942)
• Novel porphobilinogen deaminase gene mutations have been described in Polish patients with non-erythroid acute intermittent porphyria. (PMID:25923088)
• ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and HMB synthase activity was approximately half-normal (~42%) (PMID:26062020)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmbsa	ENSDARG00000008840
danio_rerio	hmbsb	ENSDARG00000055991
mus_musculus	Hmbs	ENSMUSG00000032126
rattus_norvegicus	Hmbs	ENSRNOG00000010390
drosophila_melanogaster	Hmbs	FBGN0010786

Protein

Protein identifiers

Porphobilinogen deaminase — P08397 (reviewed: P08397)

Alternative names: Hydroxymethylbilane synthase, Pre-uroporphyrinogen synthase

All UniProt accessions (15): A0A1W2PNU5, A0A3B3IRR1, A0A3B3IT17, A0A3B3IU34, A0A3B3IU56, A0A3F2YNY7, A0A8I5KXV4, P08397, F5GY90, F5H0P4, F5H226, F5H345, F5H4W5, F5H4X2, F5H4Y7

UniProt curated annotations — full annotation on UniProt →

Function. As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen. Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assembled. In the last step of catalysis, the product, preuroporphyrinogen, is released, leaving the cofactor bound to the holodeaminase intact.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Is ubiquitously expressed. Is found only in erythroid cells.

Disease relevance. Acute intermittent porphyria (AIP) [MIM:176000] A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AIP is an autosomal dominant form of hepatic porphyria characterized by attacks of gastrointestinal disturbances, abdominal colic, with neurological dysfunctions, hypertension, tachycardia and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. The disease is caused by variants affecting the gene represented in this entry. Encephalopathy, porphyria-related (ENCEP) [MIM:620704] An autosomal recessive disorder characterized by rapidly progressive neurologic abnormalities apparent in early infancy. Clinical features include global developmental delay, impaired intellectual development, hypotonia, ataxia, dysarthria, spasticity, ocular abnormalities, and peripheral neuropathy. Laboratory studies show increased plasma and urinary levels of porphyrin precursors. Death in childhood may occur. The disease is caused by variants affecting the gene represented in this entry. Leukoencephalopathy, porphyria-related (LENCEP) [MIM:620711] An autosomal recessive disorder characterized by slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 dipyrromethane group covalently.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 2/4.

Similarity. Belongs to the HMBS family.

Isoforms (4)

UniProt ID	Names	Canonical?
P08397-1	1, Non-erythropoietic	yes
P08397-2	2, Erythrocyte
P08397-3	3
P08397-4	4

RefSeq proteins (15): NP_000181, NP_001019553, NP_001245137, NP_001245138, NP_001411981, NP_001411982, NP_001411983, NP_001411985, NP_001411986, NP_001411987, NP_001411988, NP_001411990, NP_001411991, NP_001411992, NP_001411994 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000860	HemC	Family
IPR022417	Porphobilin_deaminase_N	Domain
IPR022418	Porphobilinogen_deaminase_C	Domain
IPR022419	Porphobilin_deaminase_cofac_BS	Binding_site
IPR036803	Porphobilinogen_deaminase_C_sf	Homologous_superfamily

Pfam: PF01379, PF03900

Enzyme classification (BRENDA):

• EC 2.5.1.61 — hydroxymethylbilane synthase (BRENDA: 23 organisms, 24 substrates, 81 inhibitors, 40 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PORPHOBILINOGEN	0.0011–1.579	34
HYDROXYMETHYLBILANE	0.013–0.085	4

Catalyzed reactions (Rhea), 1 shown:

• 4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+) (RHEA:13185)

UniProt features (152 total): sequence variant 102, helix 16, strand 14, modified residue 6, mutagenesis site 5, sequence conflict 3, turn 2, splice variant 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7AAK	X-RAY DIFFRACTION	1.7
7CCZ	X-RAY DIFFRACTION	1.79
7AAJ	X-RAY DIFFRACTION	1.8
7CCX	X-RAY DIFFRACTION	1.84
8PND	X-RAY DIFFRACTION	1.9
3ECR	X-RAY DIFFRACTION	2.18
7CD0	X-RAY DIFFRACTION	2.31
7CCY	X-RAY DIFFRACTION	2.4
5M6R	X-RAY DIFFRACTION	2.73
5M7F	X-RAY DIFFRACTION	2.78
3EQ1	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08397-F1	90.54	0.79

Functional residue map

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

Post-translational modifications (6): 2, 15, 69, 74, 147, 261

Mutagenesis-validated functional residues (5):

Position	Phenotype
26	loss of hydroxymethylbilane synthase activity.
34	loss of hydroxymethylbilane synthase activity.
120	decreased hydroxymethylbilane synthase activity.
120	loss of hydroxymethylbilane synthase activity.
195	loss of hydroxymethylbilane synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 439 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GNF2_PRDX2, ENK_UV_RESPONSE_KERATINOCYTE_UP, REACTOME_METABOLISM_OF_PORPHYRINS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, MODULE_335, MODULE_453, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOLDRATH_ANTIGEN_RESPONSE, GNF2_ANK1

GO Biological Process (7): obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), porphyrin-containing compound biosynthetic process (GO:0006779), peptidyl-pyrromethane cofactor linkage (GO:0018160), tetrapyrrole biosynthetic process (GO:0033014)

GO Molecular Function (3): hydroxymethylbilane synthase activity (GO:0004418), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heme biosynthetic process	2
cellular anatomical structure	2
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
porphyrin-containing compound metabolic process	1
tetrapyrrole biosynthetic process	1
peptidyl-cysteine modification	1
biosynthetic process	1
tetrapyrrole metabolic process	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HMBS	PICK1	psi-mi:“MI:0915”(physical association)	0.560
HMBS	HTT	psi-mi:“MI:0915”(physical association)	0.560
GABRE	FZD6	psi-mi:“MI:0914”(association)	0.530
Hmbs	HMBS	psi-mi:“MI:0915”(physical association)	0.400
XPO7	HMBS	psi-mi:“MI:0915”(physical association)	0.400
GSK3A	HMBS	psi-mi:“MI:0915”(physical association)	0.370
ZDHHC17	HMBS	psi-mi:“MI:0915”(physical association)	0.370
Xpo7	HAT1	psi-mi:“MI:0914”(association)	0.350
HMBS	PICK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): HMBS (Two-hybrid), HMBS (Affinity Capture-MS), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Co-fractionation), HMBS (Proximity Label-MS), HMBS (Affinity Capture-MS), HMBS (Affinity Capture-MS), HMBS (Two-hybrid), Hmbs (Affinity Capture-MS), HMBS (Two-hybrid)

ESM2 similar proteins: A3KMV5, A5D7V9, A5VYT6, B0KPI8, B1JDV7, E9QI36, O04015, O04226, O24653, O43011, O65361, P07178, P07263, P08397, P12081, P13803, P22314, P22907, P26639, P34183, P40939, P49590, P54887, P54888, P56286, P70076, Q03577, Q29504, Q29554, Q2KI84, Q2KIN5, Q3ZBV8, Q3ZC84, Q5R4R2, Q5R5E5, Q5R9I5, Q5U300, Q5XHY5, Q61035, Q64428

Diamond homologs: A1AUE7, A1JI86, A1T0R0, A1TXW9, A2BPX7, A2BVF7, A2C0V4, A2C7L8, A3PBM0, A4J6H7, A4TRA8, A5D3L5, A5GCW2, A5GSE0, A6VL87, A7FD67, A7MQJ1, A7MXU9, A8G0W4, A8G3L1, A8G848, A8GZG4, A9BEB6, A9MJ10, B0TJ54, B1JPE6, B1KQC6, B1XAH2, B2K065, B2VG55, B4TNV3, B5BIU8, B5EBG8, B5FF97, B5FN93, B6EPK1, B6I4E0, B7L959, B7LU53, B7M603

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	132
Likely pathogenic	34
Uncertain significance	270
Likely benign	236
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070047	NM_000190.4(HMBS):c.963dup (p.Asn322Ter)	Pathogenic
1070048	NM_000190.4(HMBS):c.973C>T (p.Arg325Ter)	Pathogenic
1071554	NM_000190.4(HMBS):c.982_983del (p.Gln328fs)	Pathogenic
1073659	NM_000190.4(HMBS):c.562del (p.Leu188fs)	Pathogenic
1073693	NM_000190.4(HMBS):c.57_58del (p.Arg19fs)	Pathogenic
1073990	NM_000190.4(HMBS):c.713T>C (p.Leu238Pro)	Pathogenic
1074125	NM_000190.4(HMBS):c.423-1G>A	Pathogenic
1075932	NM_000190.4(HMBS):c.148C>T (p.Gln50Ter)	Pathogenic
1075940	NM_000190.4(HMBS):c.912+2T>C	Pathogenic
1076256	NM_000190.4(HMBS):c.866_869dup (p.Ser290delinsArgTer)	Pathogenic
1120222	NM_000190.4(HMBS):c.210+1G>C	Pathogenic
1164095	NM_000190.4(HMBS):c.211-1G>T	Pathogenic
1366679	NM_000190.4(HMBS):c.498+1G>A	Pathogenic
1402568	NM_000190.4(HMBS):c.283del (p.His95fs)	Pathogenic
1412632	NM_001258208.2(HMBS):c.651+244del	Pathogenic
1441	NM_000190.4(HMBS):c.33+1G>A	Pathogenic
1443	NM_000190.4(HMBS):c.77G>A (p.Arg26His)	Pathogenic
1444	NM_000190.4(HMBS):c.33+1G>T	Pathogenic
1445	NM_000190.4(HMBS):c.346C>T (p.Arg116Trp)	Pathogenic
1447	NM_000190.4(HMBS):c.518G>A (p.Arg173Gln)	Pathogenic
1448	NM_000190.4(HMBS):c.463C>T (p.Gln155Ter)	Pathogenic
1449	NM_000190.4(HMBS):c.446G>A (p.Arg149Gln)	Pathogenic
1450	NM_000190.4(HMBS):c.734T>G (p.Leu245Arg)	Pathogenic
1451	NM_000190.4(HMBS):c.900del (p.His300fs)	Pathogenic
1453	NM_000190.4(HMBS):c.593G>A (p.Trp198Ter)	Pathogenic
1453092	NM_000190.4(HMBS):c.160+1G>T	Pathogenic
1453101	NM_000190.4(HMBS):c.825+1G>A	Pathogenic
1454	NM_000190.4(HMBS):c.91G>A (p.Ala31Thr)	Pathogenic
1455	NM_000190.4(HMBS):c.100C>A (p.Gln34Lys)	Pathogenic
1455325	NM_000190.4(HMBS):c.266+1G>A	Pathogenic

SpliceAI

2434 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119088708:G:GG	donor_gain	1.0000
11:119088762:A:T	donor_gain	1.0000
11:119089215:A:AG	acceptor_gain	1.0000
11:119089216:G:GG	acceptor_gain	1.0000
11:119089269:ATGA:A	donor_gain	1.0000
11:119089270:TGA:T	donor_gain	1.0000
11:119089271:GA:G	donor_gain	1.0000
11:119089271:GAG:G	donor_gain	1.0000
11:119089271:GAGTA:G	donor_loss	1.0000
11:119089272:AGTA:A	donor_loss	1.0000
11:119089273:GTAA:G	donor_gain	1.0000
11:119089673:A:AG	acceptor_gain	1.0000
11:119089674:T:G	acceptor_gain	1.0000
11:119089678:TATAG:T	acceptor_gain	1.0000
11:119089679:A:AG	acceptor_gain	1.0000
11:119089679:ATAGA:A	acceptor_gain	1.0000
11:119089680:T:G	acceptor_gain	1.0000
11:119089680:TAG:T	acceptor_gain	1.0000
11:119089680:TAGAG:T	acceptor_loss	1.0000
11:119089681:A:AG	acceptor_gain	1.0000
11:119089681:A:C	acceptor_loss	1.0000
11:119089681:AGA:A	acceptor_gain	1.0000
11:119089681:AGAGT:A	acceptor_gain	1.0000
11:119089682:G:C	acceptor_gain	1.0000
11:119089682:G:GA	acceptor_gain	1.0000
11:119089682:GA:G	acceptor_gain	1.0000
11:119089682:GAGT:G	acceptor_gain	1.0000
11:119089682:GAGTG:G	acceptor_gain	1.0000
11:119089757:GCAA:G	donor_gain	1.0000
11:119089758:C:T	donor_gain	1.0000

AlphaMissense

2354 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119089235:T:A	F77I	1.000
11:119089235:T:C	F77L	1.000
11:119089235:T:G	F77V	1.000
11:119089236:T:C	F77S	1.000
11:119089236:T:G	F77C	1.000
11:119089237:T:A	F77L	1.000
11:119089237:T:G	F77L	1.000
11:119089712:A:C	D99A	1.000
11:119089712:A:G	D99G	1.000
11:119089713:C:A	D99E	1.000
11:119089713:C:G	D99E	1.000
11:119091416:G:A	G168R	1.000
11:119091416:G:C	G168R	1.000
11:119091417:G:A	G168E	1.000
11:119091417:G:T	G168V	1.000
11:119088636:T:C	L30P	0.999
11:119089102:G:C	D61H	0.999
11:119089103:A:C	D61A	0.999
11:119089103:A:T	D61V	0.999
11:119089124:T:A	L68H	0.999
11:119089697:T:A	V94D	0.999
11:119089708:A:G	K98E	0.999
11:119089710:G:C	K98N	0.999
11:119089710:G:T	K98N	0.999
11:119089711:G:C	D99H	0.999
11:119089712:A:T	D99V	0.999
11:119089715:T:C	L100P	0.999
11:119090006:G:C	D121H	0.999
11:119090007:A:T	D121V	0.999
11:119090016:T:A	V124D	0.999

dbSNP variants (sampled 300 via entrez): RS1000008323 (11:119084903 G>A,C), RS1000522494 (11:119089878 G>A), RS1001069235 (11:119083787 T>C), RS1001417232 (11:119083533 T>C), RS1001906798 (11:119084162 C>T), RS1002141260 (11:119090900 C>G,T), RS1002521931 (11:119086734 G>A,T), RS1002806030 (11:119093163 C>T), RS1003209455 (11:119089806 G>A), RS1003359578 (11:119083305 ATTTTT>A,ATTTT,ATTTTTT), RS1003527451 (11:119085352 C>T), RS1003578051 (11:119085683 G>C,T), RS1003761603 (11:119092027 C>T), RS1003798360 (11:119083010 T>TTG), RS1003859933 (11:119084547 C>T)

Disease associations

OMIM: gene MIM:609806 | disease phenotypes: MIM:176000, MIM:607834, MIM:620704, MIM:620711

GenCC curated gene-disease

Disease	Classification	Inheritance
acute intermittent porphyria	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
acute intermittent porphyria	Definitive	SD

Mondo (6): acute intermittent porphyria (MONDO:0008294), anxiety (MONDO:0011918), encephalopathy, porphyria-related (MONDO:0958224), leukoencephalopathy, porphyria-related (MONDO:0958226), porphyria, acute intermittent, nonerythroid variant (MONDO:0700384), hereditary ataxia (MONDO:0100309)

Orphanet (2): Acute intermittent porphyria (Orphanet:79276), Hereditary ataxia (Orphanet:183518)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000016	Urinary retention
HP:0000020	Urinary incontinence
HP:0000083	Renal insufficiency
HP:0000280	Coarse facial features
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000725	Psychotic episodes
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000822	Hypertension
HP:0000975	Hyperhidrosis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001289	Confusion

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010241_147	Apolipoprotein A1 levels	1.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D017118	Porphyria, Acute Intermittent	C06.552.830.150; C16.320.850.742.150; C17.800.827.742.150; C18.452.811.400.150
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3988601 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.52	Ki	3000	nM	CHEMBL3901947
5.22	Ki	6000	nM	CHEMBL3976159

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Hemin	affects cotreatment, increases expression, decreases reaction, increases reaction	4
catechol	decreases methylation, increases methylation, affects cotreatment, increases expression, decreases reaction (+1 more)	3
Butyric Acid	decreases reaction, increases expression	3
hydroquinone	decreases reaction, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
Nickel	increases expression	2
Phenol	decreases reaction, increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
trichostatin A	affects expression	1
hydroxyhydroquinone	decreases reaction, increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression	1
zinc chromate	increases abundance, decreases expression	1
lead chloride	decreases activity	1
5,7-dimethoxycoumarin	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
chromium hexavalent ion	decreases expression, increases abundance	1
tellimagrandin I	decreases reaction, increases expression, decreases expression	1
CGP 52608	increases reaction, affects binding	1
chebulinic acid	decreases reaction, increases expression, decreases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
clothianidin	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3887281	Binding	Enzymatic assay: The assay is based on the method described by Jordan (Shoolingin-Jordan P M et al. (1997). Methods in enzymology 281: 327-336) with some modifications. 10 uL of porphobilinogen deaminase (PBGD) at a concentration of 150 uM	Use of inhibitors of porphobilinogen deaminase in the treatment of congenital erythropoietic porphyria

Cellosaurus cell lines

21 cell lines: 11 finite cell line, 5 transformed cell line, 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4J13	GM00931	Finite cell line	Female
CVCL_4J14	GM00932	Finite cell line	Male
CVCL_4J15	GM00933	Finite cell line	Female
CVCL_4J32	GM01621	Finite cell line	Female
CVCL_4J33	GM01622	Finite cell line	Female
CVCL_4J34	GM01623	Finite cell line	Male
CVCL_4J35	GM01624	Finite cell line	Female
CVCL_4J36	GM01625	Finite cell line	Male
CVCL_4J37	GM01647	Finite cell line	Female
CVCL_4J45	GM02124	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00174850	PHASE4	COMPLETED	Switching From an SSRI to Tiagabine(GABITRIL) in Order to Alleviate SSRI Induced Sexual Dysfunction
NCT00302107	PHASE4	COMPLETED	A Placebo-Controlled Study of Mirtazapine for PTSD
NCT00596414	PHASE4	COMPLETED	Sedation and Analgesia for Transjugular Liver Biopsy: A Randomized Double Blind Placebo Controlled Trial
NCT00623454	PHASE4	COMPLETED	Non Cardiac Chest Pain and Benign Palpitations
NCT00676364	PHASE4	COMPLETED	Randomized Control Trial of a Topical Anesthetic to Evaluate Pain and Anxiety During Venipuncture
NCT00762099	PHASE4	UNKNOWN	Perioperative Pregabalin Use, Rehabilitation, Pain Outcomes and Anxiety Following Hip Surgery
NCT00826111	PHASE4	COMPLETED	The Effects of Eszopiclone and Lexapro on Prefrontal Glutamate and GABA in Depression With Anxiety and Insomnia
NCT00928772	PHASE4	TERMINATED	Cranial Electro Therapy Stimulation in Reducing Perioperative Anxiety
NCT00951483	PHASE4	COMPLETED	Cardiovascular Biomarkers and Quetiapine in Depression and Anxiety Patients
NCT01081249	PHASE4	COMPLETED	Effects of Oxytocin on Behavior and Physiology in a Psychotherapy Setting
NCT01148186	PHASE4	TERMINATED	An Intervention Study to Reduce the Use and Impact of Potentially Inappropriate Medications Among Older Adults
NCT01155804	PHASE4	UNKNOWN	Assessment of the Effectiveness of a Program of Preparation to Pregnancy and Delivery
NCT01285284	PHASE4	UNKNOWN	Effect of Music Over the Tolerance to Colonoscopy.
NCT01309074	PHASE4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01411709	PHASE4	COMPLETED	A Study On The Effect Of Vitano® On Physiological And Psychological Responses To Psychological Stress
NCT01441843	PHASE4	COMPLETED	Resistance Under the Microscope
NCT01486615	PHASE4	COMPLETED	Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone
NCT01502644	PHASE4	COMPLETED	Opioid Treatment for Chronic Low Back Pain and the Impact of Mood Symptoms
NCT01533415	PHASE4	COMPLETED	Use of Alpha-Stim Cranial-electrotherapy Stimulation (CES) in the Treatment of Anxiety
NCT01549691	PHASE4	COMPLETED	Reassessment of Premedication in Surgery
NCT01775605	PHASE4	WITHDRAWN	Study of Use of Synera for Pain During Local Skin Infiltration With Lidocaine Before Epidural Placement
NCT01830881	PHASE4	COMPLETED	Evaluation of Oral Midazolam in First-trimester Surgical Abortions
NCT01866605	PHASE4	COMPLETED	A Study of Methods to Reduce Anxiety in Preoperative Elective Surgical Patients
NCT01993459	PHASE4	COMPLETED	The Effects of Midazolam on the Quality of Postoperative Recovery
NCT02028026	PHASE4	WITHDRAWN	The Effects of Vilazodone on Glutamate in the Anterior Cingulate Cortex in Anxious Unipolar Depressives
NCT02168439	PHASE4	COMPLETED	Intranasal Dexmedetomidine vs Intranasal Midazolam as Anxiolysis Prior to Pediatric Laceration Repair
NCT02177955	PHASE4	COMPLETED	Comparative Study of Hemodynamic Changes Caused by Diazepam and Midazolam During Third Molar Surgery
NCT02213302	PHASE4	COMPLETED	Premedication by Midazolam for Emergency Surgery
NCT02213900	PHASE4	COMPLETED	Preventing Post-Operative Delirium in Patients Undergoing a Pneumonectomy, Esophagectomy or Thoracotomy
NCT02336308	PHASE4	WITHDRAWN	A Randomized, Double-Blind Study of Placebo vs. Ketamine For Use During Dressing Changes in Critically Ill Burn Patients
NCT02366390	PHASE4	COMPLETED	Dialogue Aimed at Reducing Anxiety in Patients With Severe COPD
NCT02372110	PHASE4	COMPLETED	Disentangling Anxiety Sensitivity and Anxiety-induced Physiological Stress Response
NCT02545634	PHASE4	UNKNOWN	Effects of a Probiotic Supplement on Symptoms of Attention Deficit Hyperactivity Disorder and Anxiety in Children
NCT02618772	PHASE4	COMPLETED	Intranasal Midazolam for Treatment of Anxiety in Children Undergoing Suturing in the Pediatric Emergency Department
NCT02671578	PHASE4	COMPLETED	Bispectral Index and Clinical Parameters Evaluation in Dental Procedures
NCT03036293	PHASE4	COMPLETED	Tenoten® in the Treatment of Somatoform, Stress-related and Other Neurotic Disorders
NCT03043430	PHASE4	TERMINATED	Intranasal Ketamine for Anxiolysis in Pediatric Emergency Department Patients
NCT03078270	PHASE4	TERMINATED	A Study of the Efficacy of Botox in the Treatment of Social Anxiety Disorder
NCT03109795	PHASE4	TERMINATED	Anxiety-mediated Impairments in Large Elastic Artery Function and the Autonomic Nervous System
NCT03228628	PHASE4	UNKNOWN	Nitrous Oxide for Lumbar Puncture