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ALDH18A1 aldehyde dehydrogenase 18 family member A1 [ Homo sapiens (human) ]

Gene ID: 5832, updated on 5-Mar-2024

Summary

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Official Symbol
ALDH18A1provided by HGNC
Official Full Name
aldehyde dehydrogenase 18 family member A1provided by HGNC
Primary source
HGNC:HGNC:9722
See related
Ensembl:ENSG00000059573 MIM:138250; AllianceGenome:HGNC:9722
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
GSAS; P5CS; PYCS; SPG9; ADCL3; SPG9A; SPG9B; ARCL3A
Summary
This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]
Expression
Ubiquitous expression in duodenum (RPKM 41.4), small intestine (RPKM 34.7) and 25 other tissues See more
Orthologs
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Genomic context

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See ALDH18A1 in Genome Data Viewer
Location:
10q24.1
Exon count:
18
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 10 NC_000010.11 (95605941..95656711, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 10 NC_060934.1 (96485079..96535811, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 10 NC_000010.10 (97365698..97416468, complement)

Chromosome 10 - NC_000010.11Genomic Context describing neighboring genes Neighboring gene Sharpr-MPRA regulatory region 12220 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr10:97106670-97107322 Neighboring gene sorbin and SH3 domain containing 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2645 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2646 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3800 Neighboring gene H3K27ac hESC enhancer GRCh37_chr10:97190228-97190728 Neighboring gene Sharpr-MPRA regulatory region 10569 Neighboring gene VISTA enhancer hs2353 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr10:97291131-97291878 Neighboring gene NANOG hESC enhancer GRCh37_chr10:97299485-97299986 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr10:97311480-97312414 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr10:97320711-97321473 Neighboring gene Sharpr-MPRA regulatory region 13709 Neighboring gene Sharpr-MPRA regulatory region 3716 Neighboring gene RPS3A pseudogene 36 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2649 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3801 Neighboring gene H3K27ac hESC enhancer GRCh37_chr10:97454143-97454644 Neighboring gene MPRA-validated peak1056 silencer Neighboring gene tectonic family member 3 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3802 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3803 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3804 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2650 Neighboring gene ectonucleoside triphosphate diphosphohydrolase 1 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3805 Neighboring gene ENTPD1 antisense RNA 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2651 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3806 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3807 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3808 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3809 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3810 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3811 Neighboring gene Sharpr-MPRA regulatory region 13404

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
  • 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. Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. Colonna MB, et al. Hum Mol Genet, 2023 Feb 19. PMID 36067040, Free PMC Article
  2. SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report. Koh K, et al. BMC Neurol, 2021 Feb 11. PMID 33573605, Free PMC Article
  3. Δ(1) -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder. Marco-Marín C, et al. J Inherit Metab Dis, 2020 Jul. PMID 32017139
  4. Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. Koh K, et al. J Hum Genet, 2018 Sep. PMID 29915212
  5. Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1. Bhola PT, et al. J Hum Genet, 2017 Jun. PMID 28228640

See all (147) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.
    Title: Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.
  2. Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism.
    Title: Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism.
  3. Delta(1) -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder.
    Title: Δ(1) -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder.
  4. Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.
    Title: Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.
  5. SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report.
    Title: SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report.
  6. Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment.
    Title: Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment.
  7. This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families.
    Title: Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.
  8. ALDH18A1 gene during vertebrate and invertebrate evolution and a proposal for generating the bifunctional vertebrate and invertebrate ALDH18A1 gene from a bacterial operon (proBA) encoding glutamyl kinase and glutamyl phosphate reductase.
    Title: Comparative and evolutionary studies of ALDH18A1 genes and proteins.
  9. Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.
    Title: Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.
  10. autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment
    Title: Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.
Submit: New GeneRIF Correction See all GeneRIFs (18)

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
ALDH18A1-related de Barsy syndrome
MedGen: C5234852 OMIM: 219150 GeneReviews: Not available
Compare labs
Autosomal recessive complex spastic paraplegia type 9B
MedGen: C5568980 OMIM: 616586 GeneReviews: Not available
Compare labs
Cutis laxa, autosomal dominant 3
MedGen: C4225268 OMIM: 616603 GeneReviews: Not available
Compare labs
Hereditary spastic paraplegia 9A
MedGen: C5568978 OMIM: 601162 GeneReviews: Not available
Compare labs

EBI GWAS Catalog

Description
An atlas of genetic influences on human blood metabolites.
EBI GWAS Catalog

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

HIV-1 interactions

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Protein interactions

Protein Gene Interaction Pubs
Envelope surface glycoprotein gp120 env Tandem affinity purification and mass spectrometry analysis identify aldehyde dehydrogenase 18 family member A1 (ALDH18A1), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells PubMed
Gag-Pol gag-pol Tandem affinity purification and mass spectrometry analysis identify aldehyde dehydrogenase 18 family member A1 (ALDH18A1), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells PubMed
Nef nef Tandem affinity purification and mass spectrometry analysis identify aldehyde dehydrogenase 18 family member A1 (ALDH18A1), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells PubMed
Pr55(Gag) gag Tandem affinity purification and mass spectrometry analysis identify aldehyde dehydrogenase 18 family member A1 (ALDH18A1), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells PubMed

Go to the HIV-1, Human Interaction Database

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

Clone Names

  • MGC117316

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding IEA
Inferred from Electronic Annotation
more info
  
enables RNA binding HDA PubMed 
enables glutamate 5-kinase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables glutamate 5-kinase activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables glutamate-5-semialdehyde dehydrogenase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables glutamate-5-semialdehyde dehydrogenase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables glutamate-5-semialdehyde dehydrogenase activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables identical protein binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in L-proline biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in citrulline biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in glutamate metabolic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in ornithine biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in phosphorylation IEA
Inferred from Electronic Annotation
more info
  
involved_in proline biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in response to temperature stimulus IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
located_in mitochondrial inner membrane TAS
Traceable Author Statement
more info
  
is_active_in mitochondrion IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in mitochondrion IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
delta-1-pyrroline-5-carboxylate synthase
Names
Spastic paraplegia-9 (spastic paraparesis with amyotrophy, cataracts and gastroesophageal reflux)
aldehyde dehydrogenase family 18 member A1
delta-1-pyrroline-5-carboxylate synthetase
delta1-pyrroline-5-carboxlate synthetase
pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase)
spastic paraplegia 9 (autosomal dominant)
NP_001017423.1
NP_001310341.1
NP_001310342.1
NP_001310343.1
NP_001310344.1
NP_001310345.1
NP_001310346.1
NP_001310347.1
NP_001310348.1
NP_002851.2

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_012258.1 RefSeqGene

    Range
    5100..55870
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001017423.2 → NP_001017423.1  delta-1-pyrroline-5-carboxylate synthase isoform 2

    See identical proteins and their annotated locations for NP_001017423.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2), also known as P5Cs, uses an alternate in-frame splice site, compared to variant 1, resulting in a shorter isoform (2). Variants 2 and 6 both encode the same isoform (2).
    Source sequence(s)
    AW467503, BU170321, CD642171, U68758, X94453
    Consensus CDS
    CCDS31257.1
    UniProtKB/Swiss-Prot
    P54886
    Related
    ENSP00000360265.3, ENST00000371221.3
    Conserved Domains (1) summary
    TIGR01092
    Location:64 → 792
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  2. NM_001323412.2 → NP_001310341.1  delta-1-pyrroline-5-carboxylate synthase isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) and variant 7 both encode isoform 3.
    Source sequence(s)
    AL356632
    UniProtKB/Swiss-Prot
    P54886
    Conserved Domains (1) summary
    TIGR01092
    Location:1 → 683
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  3. NM_001323413.2 → NP_001310342.1  delta-1-pyrroline-5-carboxylate synthase isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) and variants 1 and 5 all encode isoform 1.
    Source sequence(s)
    AL356632
    Consensus CDS
    CCDS7443.1
    UniProtKB/Swiss-Prot
    B2R5Q4, B7Z350, B7Z5X8, B7ZLP1, D3DR44, O95952, P54886, Q3KQU2, Q5T566, Q5T567, Q9UM72
    Conserved Domains (1) summary
    TIGR01092
    Location:64 → 794
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  4. NM_001323414.2 → NP_001310343.1  delta-1-pyrroline-5-carboxylate synthase isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) and variants 1 and 4 all encode isoform 1.
    Source sequence(s)
    AL356632
    Consensus CDS
    CCDS7443.1
    UniProtKB/Swiss-Prot
    B2R5Q4, B7Z350, B7Z5X8, B7ZLP1, D3DR44, O95952, P54886, Q3KQU2, Q5T566, Q5T567, Q9UM72
    Conserved Domains (1) summary
    TIGR01092
    Location:64 → 794
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  5. NM_001323415.2 → NP_001310344.1  delta-1-pyrroline-5-carboxylate synthase isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (6) and variant 2 both encode isoform 2.
    Source sequence(s)
    AL356632
    Consensus CDS
    CCDS31257.1
    UniProtKB/Swiss-Prot
    P54886
    Conserved Domains (1) summary
    TIGR01092
    Location:64 → 792
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  6. NM_001323416.2 → NP_001310345.1  delta-1-pyrroline-5-carboxylate synthase isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (7) and variant 3 both encode isoform 3.
    Source sequence(s)
    AL356632
    UniProtKB/Swiss-Prot
    P54886
    Conserved Domains (1) summary
    TIGR01092
    Location:1 → 683
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  7. NM_001323417.2 → NP_001310346.1  delta-1-pyrroline-5-carboxylate synthase isoform 4

    Status: REVIEWED

    Source sequence(s)
    AL356632

  8. NM_001323418.2 → NP_001310347.1  delta-1-pyrroline-5-carboxylate synthase isoform 5

    Status: REVIEWED

    Source sequence(s)
    AL356632
    Conserved Domains (1) summary
    TIGR01092
    Location:1 → 681
    P5CS; delta l-pyrroline-5-carboxylate synthetase

  9. NM_001323419.2 → NP_001310348.1  delta-1-pyrroline-5-carboxylate synthase isoform 6

    Status: REVIEWED

    Source sequence(s)
    AK299557, AL356632
    UniProtKB/Swiss-Prot
    P54886
    Conserved Domains (2) summary
    cd07079
    Location:152 → 554
    ALDH_F18-19_ProA-GPR; Gamma-glutamyl phosphate reductase (GPR), aldehyde dehydrogenase families 18 and 19
    cl00452
    Location:1 → 142
    AAK; Amino Acid Kinases (AAK) superfamily, catalytic domain; present in such enzymes like N-acetylglutamate kinase (NAGK), carbamate kinase (CK), aspartokinase (AK), glutamate-5-kinase (G5K) and UMP kinase (UMPK). The AAK superfamily includes kinases that ...

  10. NM_002860.4 → NP_002851.2  delta-1-pyrroline-5-carboxylate synthase isoform 1

    See identical proteins and their annotated locations for NP_002851.2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1), also known as P5CSL, encodes the longest isoform (1). Variants 1, 4, and 5 all encode the same isoform (1).
    Source sequence(s)
    AW467503, BU170321, CD642171, U76542, X94453
    Consensus CDS
    CCDS7443.1
    UniProtKB/Swiss-Prot
    B2R5Q4, B7Z350, B7Z5X8, B7ZLP1, D3DR44, O95952, P54886, Q3KQU2, Q5T566, Q5T567, Q9UM72
    Related
    ENSP00000360268.2, ENST00000371224.7
    Conserved Domains (1) summary
    TIGR01092
    Location:64 → 794
    P5CS; delta l-pyrroline-5-carboxylate synthetase

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

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

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000010.11 Reference GRCh38.p14 Primary Assembly

    Range
    95605941..95656711 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060934.1 Alternate T2T-CHM13v2.0

    Range
    96485079..96535811 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P54886.2 GenPept UniProtKB/Swiss-Prot:P54886

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