Alternative titles; symbols
HGNC Approved Gene Symbol: ALDH18A1
SNOMEDCT: 1187465008, 1187467000, 1295485009;
Cytogenetic location: 10q24.1 Genomic coordinates (GRCh38): 10:95,605,941-95,656,711 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.1 | Cutis laxa, autosomal dominant 3 | 616603 | Autosomal dominant | 3 |
| Cutis laxa, autosomal recessive, type IIIA | 219150 | Autosomal recessive | 3 | |
| Spastic paraplegia 9A, autosomal dominant | 601162 | Autosomal dominant | 3 | |
| Spastic paraplegia 9B, autosomal recessive | 616586 | Autosomal recessive | 3 |
The ALDH18A1 gene encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), which catalyzes the first 2 steps of the de novo biosynthesis of proline, ornithine, and arginine. The enzyme is bifunctional, converting glutamate into P5C in 2 steps, catalyzed sequentially by the L-glutamate 5-kinase (G5K) and L-glutamyl-5-phosphate reductase (G5PR) domains (summary by Panza et al., 2016).
By a method they referred to as 'database cloning,' Aral et al. (1996) isolated and sequenced a cDNA encoding the human P5CS gene.
Hu et al. (1999) observed that mammalian P5CS undergoes alternative splicing to generate 2 isoforms differing only by a 2-amino acid insert at the N terminus of the gamma-glutamyl kinase active site. The short isoform has high activity in the gut, where it participates in arginine biosynthesis and is inhibited by ornithine. The long isoform, expressed in multiple tissues, is necessary for the synthesis of proline from glutamate and is insensitive to ornithine.
Jones (1975) presented evidence from cell hybrid studies that the structural gene for the enzyme converting glutamate to its gamma semialdehyde is located on chromosome 10. The fact that glutamate-gamma-semialdehyde synthetase (GSAS) and glutamate oxaloacetate transaminase (138180) are in the same biochemical pathway and determined by genes on the same chromosome may have biologic significance (Jones, 1975).
By fluorescence in situ hybridization, Liu et al. (1996) mapped the PYCS gene to 10q24.3.
Cutis Laxa, Autosomal Recessive, Type IIIA
Baumgartner et al. (2000) observed homozygosity for a missense mutation in P5CS in the 2 sibs described by Rabier et al. (1992) with mental retardation, joint hypermobility, skin hyperelasticity, cataract, and metabolic abnormalities, including hyperammonemia, hypoprolinemia, hypocitrullinemia, and hypoornithinemia (ARCL3A; 219150). The arg84-to-gln mutation (R84Q; 138250.0001) alters a conserved residue in the P5CS gamma-glutamyl kinase domain and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells. Additionally, R84Q appears to destabilize the long isoform.
In affected individuals from a New Zealand family with mental retardation, joint hypermobility, and skin laxity without metabolic abnormalities, Bicknell et al. (2008) identified a homozygous mutation in the ALDH18A1 gene (H784Y; 138250.0002). In vitro functional expression studies indicated that the H784Y mutant protein retained normal P5CS activity and did not impair proline synthesis. The findings indicated that impaired enzymatic activity does not account for the phenotype, as was suggested for the patients reported by Baumgartner et al. (2000).
Skidmore et al. (2011) reported a child born of a consanguineous union with features consistent with de Barsy syndrome (ARCL3A) with homozygous mutation in the ALDH18A1 gene (138250.0003).
Fischer et al. (2014) reported 2 additional patients with de Barsy syndrome (ARCL3A) who had mutations in the ALDH18A1 gene. One was homozygous for a deletion of exon 15 (138250.0004). The other patient was homozygous for a frameshift due to the deletion of a single nucleotide in ALDH18A1 (138250.0005). Levels of mRNA from fibroblasts of both patients were severely reduced compared to control fibroblasts.
In a 2-year-old boy with cutis laxa, abnormal fat pad distribution, and retinopathy, who was negative for mutation in the ATP6V0A1 (611716), COG7 (606978), GORAB (607983), and PYCR1 genes, Wolthuis et al. (2014) performed whole-exome sequencing and identified homozygosity for a missense mutation in the ALDH18A1 gene (Y780C; 138250.0016).
In a fetus from a terminated pregnancy at 27 weeks' gestation, Lefebvre et al. (2018) identified compound heterozygous mutations in the ALDH18A1 gene (R425C, 138250.0017 and c.177delG, 138250.0018). The mutations were identified by whole-exome sequencing. Functional studies were not performed.
In 4 patients, including 3 sibs, from 2 families with ARCL3A, Colonna et al. (2023) identified a homozygous mutation in the ALDH18A1 gene (T331P; 138250.0019). In an HEK293 cell line expressing ALDH18A1 with the T331P mutation, the mutant ALDH18A1 had comparable expression levels to wildtype and normal mitochondrial localization. However, analysis in fibroblasts from patient 2 demonstrated that the mutant P5CS protein had decreased oligomerization compared to wildtype. Metabolomic analysis in patient fibroblasts demonstrated decreased proline, glutamine, glutathione, and putrescine compared to wildtype. Colonna et al. (2023) hypothesized that the decreased glutathione reflected increased oxidative stress in patient cells and that the decreased putrescine may have reflected increased flux towards synthesis of spermidine and spermine as part of an antioxidant response. Transcriptomic analysis in patient fibroblasts showed dysregulation of genes involved in glutathione metabolism and increased expression of MMP3 (185250) and COMP (600310), which are involved with extracellular matrix metabolism.
Cutis Laxa, Autosomal Dominant 3
In 8 unrelated children with a progeroid de Barsy-like cutis laxa phenotype (ADCL3; 616603), Fischer-Zirnsak et al. (2015) identified heterozygosity for 3 different missense mutations in the ALDH18A1 gene, all involving the highly conserved arg138 residue (R138W, R138Q, and R138L; 138250.0013-138250.0015). In all 6 families for which parental DNA was available, the mutation was shown to have arisen de novo. Studies in patient fibroblasts demonstrated that the R138W mutant protein had an altered submitochondrial distribution and reduced enzymatic activity compared to wildtype.
Spastic Paraplegia, Autosomal Dominant 9A
In affected members of 3 unrelated families with autosomal dominant spastic paraplegia-9A (SPG9A; 601162), Coutelier et al. (2015) identified heterozygous missense mutations in the ALDH18A1 gene (138250.0007-138250.0009). Two patients with sporadic occurrence of the disorder also carried heterozygous missense variants in ALDH18A1. The mutations were found by whole-exome or panel sequencing and segregated with the disorder in the families. Fibroblasts from 2 patients of 1 family with the V120A mutation (138250.0008) showed decreased (42%) residual flux of proline biosynthesis compared to controls, consistent with an enzymatic deficiency. Functional studies of the other variants were not performed.
Panza et al. (2016) identified heterozygous missense mutations in the ALDH18A1 gene in 2 additional families with autosomal dominant SPG9A (138250.0006 and 138250.0007). The mutations were found by candidate gene sequencing and segregated with the disorder in the families. In vitro functional expression assays showed that the mutant proteins localized normally to the mitochondria, but had low P5CS and G5K enzymatic activity; G5PR enzymatic activity was close to normal. Chromatography studies indicated that the mutations disturbed the architecture of the P5CS hexamer, putatively resulting in a dominant-negative effect.
Spastic Paraplegia, Autosomal Recessive 9B
In affected members of 2 unrelated families with autosomal recessive spastic paraplegia-9B (SPG9B; 601162), Coutelier et al. (2015) identified homozygous or compound heterozygous missense mutations in the ALDH18A1 gene (138250.0010-138250.0012). The mutations were found by whole-exome or panel sequencing. Functional studies of the variants were not performed.
Baumgartner et al. (2000) determined that the 2 sibs reported by Rabier et al. (1992) with mental retardation, joint hypermobility, skin laxity, cataracts, and metabolic abnormalities (219150) were homozygous for a 251G-A transition of the PYCS gene, resulting in an arg84-to-gln (R84Q) substitution. The mutation impairs the function of both the long and short isoforms of PYCS.
In 4 affected sibs, born of consanguineous New Zealand Maori parents, with mental retardation, joint hypermobility, skin laxity without metabolic abnormalities (219150), Bicknell et al. (2008) identified a homozygous 2350C-T transition in exon 18 of the ALDH18A1 gene, resulting in a his784-to-tyr (H784Y) substitution in a conserved residue in the C-terminal motif. In vitro functional expression studies indicated that the H784Y-mutant protein retained normal P5CS activity and did not impair proline synthesis. The findings indicated that impaired enzymatic activity does not account for the phenotype.
In a severely affected child with clinical features consistent with de Barsy syndrome (ARCL3A; 219150), born to consanguineous parents of Pakistani origin, Skidmore et al. (2011) reported homozygosity for a G-to-A transition at the exon 14-intron 14 boundary (nucleotide 1923+1) of the ALDH18A1 gene. The mutation resulted in 2 anomalous transcripts that were predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype was characterized by diminished production of collagens type I (see 120150) and III (see 120180), altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. The child had lax, wrinkled, and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child also had severe global developmental delay and feeding difficulties, and died in infancy of unknown causes.
In a female patient with severe de Barsy syndrome (ARCL3A; 219150), the first child of a consanguineous Tunisian couple, Fischer et al. (2014) identified homozygosity for a 1,522-bp microdeletion in the ALDH18A1 gene comprising exon 15 and flanking intronic sequence (chr10:97,373,623-97,372,101; GRCh37), and insertion of a guanosine. The deletion led to a frameshift with a predicted premature termination codon after 24 additional codons (Val601GlyfsTer24).
Fischer et al. (2014) reported a male patient with severe de Barsy syndrome (ARCL3A; 219150), born to a consanguineous Turkish couple, who was homozygous for a single-basepair deletion, c.2131delC, in exon 17 of the ALDH18A1 gene. This alteration led to a frameshift and a predicted termination of translation after 3 additional codons (Leu711CysfsTer3).
In affected members of a large Italian family with autosomal dominant spastic paraplegia-9A (SPG9A; 601162), originally reported by Seri et al. (1999), Panza et al. (2016) identified a heterozygous c.727G-C transversion in the ALDH18A1 gene, resulting in a val243-to-leu (V243L) substitution at a highly conserved residue in the G5K domain. The mutation, which was found by a combination of candidate gene sequencing and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 446 control chromosomes. Patient cells showed decreased (about 45%) levels of the mutant protein compared to controls, but the mutant protein localized normally to the mitochondria. In vitro functional expression assays showed that the mutant protein had low P5CD and G5K enzymatic activity, but retained G5PR enzymatic activity close to normal. Chromatography studies indicated that the mutation disturbed the architecture of the P5CS hexamer, putatively resulting in a dominant-negative effect.
In affected members of a French family (FSP470) with spastic paraplegia-9A (SPG9A; 601162) and in a patient (patient 25014) with sporadic occurrence of the disorder, Coutelier et al. (2015) identified a heterozygous c.755G-A transition (c.755G-A, NM_002860.3) in the ALDH18A1 gene, resulting in an arg252-to-gln (R252Q) substitution. Haplotype analysis excluded a founder effect. Functional studies of the variant were not performed.
In affected members of an British family with autosomal dominant SPG9A, originally reported by Slavotinek et al. (1996), Panza et al. (2016) identified heterozygosity for the c.755G-A transition in the ALDH18A1 gene, resulting in an R252Q substitution at a highly conserved residue in the G5K domain. The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 446 control chromosomes. In vitro functional expression assays showed that the mutant protein localized normally to the mitochondria, but had low P5CS and G5K enzymatic activity; G5PR enzymatic activity was close to normal. Chromatography studies indicated that the mutation disturbed the architecture of the P5CS hexamer, putatively resulting in a dominant-negative effect.
In affected members of a family (FSP410) with autosomal dominant spastic paraplegia-9A (SPG9A; 601162), Coutelier et al. (2015) identified a heterozygous c.359T-C transition (c.359T-C, NM_002860.3) in the ALDH18A1 gene, resulting in a val120-to-ala (V120A) substitution at a highly conserved residue in the G5K domain (Panza et al., 2016). The mutation, which was found by whole-exome or panel sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138), Exome Variant Server, or ExAC databases. Patient fibroblasts showed decreased (42%) residual flux of proline biosynthesis compared to controls, consistent with an enzymatic deficiency.
In affected members of a French family (FSP429) with autosomal dominant spastic paraplegia-9A (SPG9A; 601162), Coutelier et al. (2015) identified a heterozygous c.1994G-T transversion (c.1994G-T, NM_002860.3) in the ALDH18A1 gene, resulting in an arg665-to-leu (R665L) substitution at a highly conserved residue in the G5PR domain (Panza et al., 2016). The mutation, which was found by whole-exome or panel sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138), Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed.
In 4 sibs from a Spanish family (FSP856) with autosomal recessive spastic paraplegia-9B (SPG9B; 616586), Coutelier et al. (2015) identified a homozygous c.2143G-C transversion (c.2143G-C, NM_002860.3) in the ALDH18A1 gene, resulting in an asp715-to-his (D715H) substitution at a conserved residue in the G5PR domain (Panza et al., 2016). The mutation, which was found by whole-exome or panel sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138) or Exome Variant Server databases; it was present at a very low frequency in the ExAC database. Functional studies of the variant was not performed.
In 2 brothers from a Portuguese family (SR45) with autosomal recessive spastic paraplegia-9B (SPG9B; 616586), Coutelier et al. (2015) identified compound heterozygous missense mutations in the ALDH18A1 gene: a c.1910T-C transition (c.1910T-C, NM_002860.3), resulting in a leu637-to-pro (L637P) substitution at a conserved residue in the G5PR domain, and a c.383G-A transition, resulting in an arg128-to-his (R128H; 138250.0012) substitution at a conserved residue in the G5K domain. The mutations, which were found by whole-exome or panel sequencing, were not found in the dbSNP (build 138) or Exome Variant Server databases; In the ExAC database, L637P was also absent, whereas there was 1 homozygous carrier of the R128H variant. Functional studies of the variants were not performed.
For discussion of the c.383G-A transition (c.383G-A, NM_002860.3) in the ALDH18A1 gene, resulting in an arg128-to-his (R128H) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive spastic paraplegia-9B (SPG9B; 616586) by Coutelier et al. (2015), see 138250.0011.
In 3 unrelated children with a progeroid de Barsy-like cutis laxa phenotype (ADCL3; 616603), 1 of whom was originally reported by Jukkola et al. (1998), Fischer-Zirnsak et al. (2015) identified heterozygosity for a c.412C-T transition (c.412C-T, NM_002860.3) in the ALDH18A1 gene, resulting in an arg138-to-trp (R138W) substitution at a highly conserved residue in the alpha-glutamyl kinase domain. Analysis of parental DNA showed that the mutation arose de novo in all 3 patients; scrutiny of nearby SNPs in 2 of the probands indicated that the mutation arose on the paternal allele. The mutation was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project datasets. Functional analysis of patient fibroblasts demonstrated an altered submitochondrial localization of the R138W mutant compared to wildtype, as well as reduced enzymatic activity.
In 3 unrelated children with a progeroid de Barsy-like cutis laxa phenotype (ADCL3; 616603), Fischer-Zirnsak et al. (2015) identified heterozygosity for a c.413G-A transition (c.413G-A, NM_002860.3) in the ALDH18A1 gene, resulting in an arg138-to-gln (R138Q) substitution at a highly conserved residue in the alpha-glutamyl kinase domain. Analysis of parental DNA in the 2 families for which it was available showed that the mutation arose de novo in both cases.
In 2 unrelated children with a progeroid de Barsy-like cutis laxa phenotype (ADCL3; 616603), Fischer-Zirnsak et al. (2015) identified heterozygosity for a c.413G-T transversion (c.413G-T, NM_002860.3) in the ALDH18A1 gene, resulting in an arg138-to-leu (R138L) substitution at a highly conserved residue in the alpha-glutamyl kinase domain. Analysis of parental DNA in 1 family for which it was available showed that the mutation arose de novo.
In a 2-year-old boy with cutis laxa (ARCL3A; 219150), who also had abnormal fat pad distribution and retinopathy, Wolthuis et al. (2014) identified homozygosity for a c.2339T-C transition in exon 18 of the ALDH18A1 gene, resulting in a tyr780-to-cys (Y780C) substitution. DNA from his consanguineous parents was unavailable, but the mutation was not found in 100 ethnically matched controls, 2,800 in-house exomes, or the Exome Variant Server database.
In a fetus of 27 weeks' gestation with autosomal recessive cutis laxa IIIA (ARCL3A; 219150), Lefebvre et al. (2018) identified compound heterozygous mutations in the ALDH18A1 gene: a c.1273C-T transition, resulting in an arg425-to-cys (R425C) substitution, and a 1-bp deletion (c.177delG; 138250.0018), resulting in a frameshift and premature termination (Lys59AsnfsTer9). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents. The R425C mutation was present at an allele frequency of 0.008924% in the ExAC database and the c.177delG mutation was not present in the ExAC database.
For discussion of the 1-bp deletion (c.177delG, NM_002860.3) in the ALDH18A1 gene, resulting in a frameshift and premature termination (Lys59AsnfsTer9), that was identified in compound heterozygous state in a fetus of 27 weeks' gestation with autosomal recessive cutis laxa IIIA (ARCL3A; 219150) by Lefebvre et al. (2018), see 138250.0017.
In 4 patients, including 3 sibs, from 2 families with autosomal recessive cutis laxa IIIA (ARCL3A; 219150), Colonna et al. (2023) identified homozygosity for a c.991A-C transversion (c.991A-C, NM_002860.3) in the ALDH18A1 gene, resulting in a thr331-to-pro (T331P) substitution. The mutation, which was identified by whole-exome sequencing, segregated with disease in both families. Analysis in fibroblasts from one of the sibs (patient 2) demonstrated that the mutant P5CS protein had decreased oligomerization compared to wildtype. (In the article by Colonna et al. (2023), the nucleotide change is stated as c.991G-T on page 734, but as c.991A-C on page 735.)
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