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HMBS hydroxymethylbilane synthase [ Homo sapiens (human) ]

Gene ID: 3145, updated on 14-Nov-2024

Summary

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Official Symbol
HMBSprovided by HGNC
Official Full Name
hydroxymethylbilane synthaseprovided by HGNC
Primary source
HGNC:HGNC:4982
See related
Ensembl:ENSG00000256269 MIM:609806; AllianceGenome:HGNC:4982
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
UPS; PBGD; PORC; ENCEP; PBG-D; LENCEP
Summary
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. [provided by RefSeq, Jul 2008]
Expression
Biased expression in bone marrow (RPKM 55.8), colon (RPKM 5.0) and 13 other tissues See more
Orthologs
mouse all
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Genomic context

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See HMBS in Genome Data Viewer
Location:
11q23.3
Exon count:
16
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 11 NC_000011.10 (119084881..119093549)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 11 NC_060935.1 (119105272..119113932)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 11 NC_000011.9 (118955591..118964259)

Chromosome 11 - NC_000011.10Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124902769 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 5619 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 5620 Neighboring gene VPS11 core subunit of CORVET and HOPS complexes Neighboring gene H3K27ac hESC enhancer GRCh37_chr11:118955192-118955889 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:118963458-118963970 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:118965105-118965668 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:118965669-118966232 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:118966233-118966796 Neighboring gene H3K27ac hESC enhancer GRCh37_chr11:118966797-118967358 Neighboring gene dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 Neighboring gene H2A.X variant histone Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr11:118972216-118973415 Neighboring gene C2CD2 like Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3968 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3969

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Neurodevelopmental disorder in a patient with HMBS and SCN3A variants-A possibly blended phenotype further delineating autosomal recessive HMBS related disease.
    Title: Neurodevelopmental disorder in a patient with HMBS and SCN3A variants-A possibly blended phenotype further delineating autosomal recessive HMBS related disease.
  2. Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria.
    Title: Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria.
  3. Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.
    Title: Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.
  4. Two Novel Hydroxymethylbilane Synthase Splicing Mutations Predispose to Acute Intermittent Porphyria.
    Title: Two Novel Hydroxymethylbilane Synthase Splicing Mutations Predispose to Acute Intermittent Porphyria.
  5. Brain ventricular enlargement in human and murine acute intermittent porphyria.
    Title: Brain ventricular enlargement in human and murine acute intermittent porphyria.
  6. Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 315 unrelated Acute Intermittent Porphyria individuals with HMBS mutations, including 46 previously unreported mutations.
    Title: Acute hepatic porphyrias: Identification of 46 hydroxymethylbilane synthase, 11 coproporphyrinogen oxidase, and 20 protoporphyrinogen oxidase novel mutations.
  7. Identified 40 novel HMBS mutations in unrelated individuals with acute intermittent porphyria (AIP); all mutants had less than 5% of expressed wildtype activity, except for c.1039G>C (p.A347P), which had 51% residual HMBS activity. Mutations near the active site or at the dimerization interface resulted in stably expressed proteins, while most that altered surface residues resulted in unstable protein.
    Title: Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria.
  8. To investigate the dramatically different manifestations, knock-in mice with human homozygous dominant-Acute intermittent porphyria (HD-AIP) missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype
    Title: Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.
  9. Using two bioinformatics pipelines for analysis of RNA fingerprints we identified significant effects of E. coli on the mRNAs HMBS, ATP2C1 and LRCH4. To see whether these three proteins were present in platelets and were influenced by the bacteria, we analysed HMBS, ATP2C1 and LRCH4 in platelet lysates and releasates by Western blot and ELISA.
    Title: Impact of Escherichia coli K12 and O18:K1 on human platelets: Differential effects on platelet activation, RNAs and proteins.
  10. In the present study, we identified four HMBS gene mutations affecting the ubiquitous isoform of porphobilinogen deaminase (PBGD) and established a dPCR protocol which would be able to detect the different transcripts of this gene.
    Title: Molecular characterization, by digital PCR analysis of four HMBS gene mutations affecting the ubiquitous isoform of Porphobilinogen Deaminase (PBGD) in patients with Acute Intermittent Porphyria (AIP).
Submit: New GeneRIF Correction See all GeneRIFs (59)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Acute intermittent porphyria
MedGen: C0162565 OMIM: 176000 GeneReviews: Acute Intermittent Porphyria
Compare labs
Encephalopathy, porphyria-related
MedGen: CN376852 OMIM: 620704 GeneReviews: Not available
Compare labs
Leukoencephalopathy, porphyria-related
MedGen: CN376853 OMIM: 620711 GeneReviews: Not available
not available

Copy number response

Description
Copy number response
Triplosensitivity

No evidence available (Last evaluated 2020-01-08)

ClinGen Genome Curation Page
Haploinsufficency

Sufficient evidence for dosage pathogenicity (Last evaluated 2020-01-08)

ClinGen Genome Curation PagePubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables hydroxymethylbilane synthase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables hydroxymethylbilane synthase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables hydroxymethylbilane synthase activity TAS
Traceable Author Statement
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in heme A biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in heme B biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in heme O biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in heme biosynthetic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in heme biosynthetic process IC
Inferred by Curator
more info
 PubMed 
involved_in heme biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in heme biosynthetic process TAS
Traceable Author Statement
more info
  
involved_in protoporphyrinogen IX biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
is_active_in cytoplasm IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in cytosol TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
porphobilinogen deaminase
Names
porphyria, acute; Chester type
pre-uroporphyrinogen synthase
uroporphyrinogen I synthase
uroporphyrinogen I synthetase
NP_000181.2
NP_001019553.1
NP_001245137.1
NP_001245138.1
NP_001411981.1
NP_001411982.1
NP_001411983.1
NP_001411985.1
NP_001411986.1
NP_001411987.1
NP_001411988.1
NP_001411990.1
NP_001411991.1
NP_001411992.1
NP_001411994.1
XP_011541098.1
XP_016873118.1
XP_054224575.1
XP_054224577.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_008093.1 RefSeqGene

    Range
    5005..13673
    Download
    GenBank, FASTA, Sequence Viewer (Graphics), LRG_1076

mRNA and Protein(s)

  1. NM_000190.4 → NP_000181.2  porphobilinogen deaminase isoform 1

    See identical proteins and their annotated locations for NP_000181.2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
    Source sequence(s)
    AW139390, BC019323, CB128006
    Consensus CDS
    CCDS8409.1
    UniProtKB/Swiss-Prot
    A8K2L0, G3V1P4, G5EA58, P08396, P08397, Q16012
    UniProtKB/TrEMBL
    A0A3B3IRR1
    Related
    ENSP00000498786.1, ENST00000652429.1
    Conserved Domains (1) summary
    cd13645
    Location:20 → 299
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

  2. NM_001024382.2 → NP_001019553.1  porphobilinogen deaminase isoform 2

    See identical proteins and their annotated locations for NP_001019553.1

    Status: REVIEWED

    Source sequence(s)
    AA724756, AP003391, BX647328, X04217
    Consensus CDS
    CCDS41726.1
    UniProtKB/TrEMBL
    A0A3B3IRR1
    Related
    ENSP00000376584.1, ENST00000392841.1
    Conserved Domains (1) summary
    cd13645
    Location:3 → 282
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

  3. NM_001258208.2 → NP_001245137.1  porphobilinogen deaminase isoform 3

    See identical proteins and their annotated locations for NP_001245137.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (3) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AK131072, AW139390, CB128006
    Consensus CDS
    CCDS58186.1
    UniProtKB/TrEMBL
    F5H345
    Related
    ENSP00000438424.1, ENST00000544387.5
    Conserved Domains (2) summary
    PRK00072
    Location:18 → 304
    hemC; porphobilinogen deaminase; Reviewed
    cd13645
    Location:20 → 259
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

  4. NM_001258209.2 → NP_001245138.1  porphobilinogen deaminase isoform 4

    See identical proteins and their annotated locations for NP_001245138.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) uses an alternate splice junction at the 3' end of the first exon and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (4) is shorter at the N-terminus and lacks an alternate internal segment compared to isoform 1.
    Source sequence(s)
    AK000628, AP003392, AW139390, CB128006
    Consensus CDS
    CCDS58187.1
    UniProtKB/TrEMBL
    A0A3B3IRR1
    Related
    ENSP00000443058.1, ENST00000542729.5
    Conserved Domains (2) summary
    PRK00072
    Location:1 → 287
    hemC; porphobilinogen deaminase; Reviewed
    cd13645
    Location:3 → 242
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

  5. NM_001425052.1 → NP_001411981.1  porphobilinogen deaminase isoform 2

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    Related
    ENSP00000444730.1, ENST00000537841.5

  6. NM_001425053.1 → NP_001411982.1  porphobilinogen deaminase isoform 2

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392

  7. NM_001425054.1 → NP_001411983.1  porphobilinogen deaminase isoform 2

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    Related
    ENSP00000496970.1, ENST00000650101.1

  8. NM_001425056.1 → NP_001411985.1  porphobilinogen deaminase isoform 5

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392

  9. NM_001425057.1 → NP_001411986.1  porphobilinogen deaminase isoform 6

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    UniProtKB/TrEMBL
    A0A3F2YNY7
    Related
    ENSP00000392041.3, ENST00000442944.7

  10. NM_001425058.1 → NP_001411987.1  porphobilinogen deaminase isoform 7

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392

  11. NM_001425059.1 → NP_001411988.1  porphobilinogen deaminase isoform 8

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    Related
    ENSP00000445429.1, ENST00000543090.5

  12. NM_001425061.1 → NP_001411990.1  porphobilinogen deaminase isoform 9

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392

  13. NM_001425062.1 → NP_001411991.1  porphobilinogen deaminase isoform 10

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    UniProtKB/TrEMBL
    A0A8I5KXV4

  14. NM_001425063.1 → NP_001411992.1  porphobilinogen deaminase isoform 10

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392
    UniProtKB/TrEMBL
    A0A8I5KXV4

  15. NM_001425065.1 → NP_001411994.1  porphobilinogen deaminase isoform 11

    Status: REVIEWED

    Source sequence(s)
    AP003391, AP003392

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000011.10 Reference GRCh38.p14 Primary Assembly

    Range
    119084881..119093549
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_017017629.2 → XP_016873118.1  porphobilinogen deaminase isoform X1

    UniProtKB/TrEMBL
    A0A3B3IRR1
    Related
    ENSP00000497255.1, ENST00000648374.1
    Conserved Domains (1) summary
    cd13645
    Location:3 → 282
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

  2. XM_011542796.2 → XP_011541098.1  porphobilinogen deaminase isoform X3

    UniProtKB/TrEMBL
    A0A3B3IRR1, A0A8I5KXV4
    Related
    ENSP00000509288.1, ENST00000686218.1
    Conserved Domains (1) summary
    cd13645
    Location:1 → 244
    PBP2_HuPBGD_like; Human porphobilinogen deaminase possess type 2 periplasmic binding protein fold

Reference GRCh38.p14 PATCHES

Genomic

  1. NW_009646203.1 Reference GRCh38.p14 PATCHES

    Range
    106480..107495
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060935.1 Alternate T2T-CHM13v2.0

    Range
    119105272..119113932
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054368600.1 → XP_054224575.1  porphobilinogen deaminase isoform X1

  2. XM_054368602.1 → XP_054224577.1  porphobilinogen deaminase isoform X3

    UniProtKB/TrEMBL
    A0A8I5KXV4
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P08397.2 GenPept UniProtKB/Swiss-Prot:P08397

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