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    HMBS hydroxymethylbilane synthase [ Homo sapiens (human) ]

    Gene ID: 3145, updated on 2-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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    Related articles in PubMed

    1. Acute intermittent porphyria: heterogeneity of mutations in the hydroxymethylbilane synthase gene in Italy. Martinez di Montemuros F, et al. Blood Cells Mol Dis, 2001 Nov-Dec. PMID 11831862
    2. Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families. Lundin G, et al. Hum Genet, 1997 Jul. PMID 9225970
    3. Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria. Ong PM, et al. Hum Hered, 1998 Jan-Feb. PMID 9463797
    4. Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria. Mustajoki S, et al. Hum Genet, 1998 May. PMID 9654202
    5. Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation. De Siervi A, et al. Am J Med Genet, 1999 Oct 8. PMID 10494093

    See all (143) citations in PubMed

    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)

    Genotypes

    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 peptidyl-pyrromethane cofactor linkage IEA
    Inferred from Electronic Annotation
    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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