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PYRROLINE-5-CARBOXYLATE REDUCTASE 2; PYCR2

PYRROLINE-5-CARBOXYLATE REDUCTASE 2; PYCR2

HGNC Approved Gene Symbol: PYCR2Cytogenetic location: 1q42.12 Genomic coordinates (GRCh38): 1:225,919,877-225,924,249 (from NCBI)▼ DescriptionPyrroline-5-car...

HGNC Approved Gene Symbol: PYCR2

Cytogenetic location: 1q42.12 Genomic coordinates (GRCh38): 1:225,919,877-225,924,249 (from NCBI)

▼ Description
Pyrroline-5-carboxylate reductase (EC 1.5.1.2) is a mitochondrial enzyme that catalyzes the final step of proline biosynthesis and reduces pyrroline-5-carboxylate (P5C) to L-proline using NADH as cofactor (summary by De Ingeniis et al., 2012).

▼ Cloning and Expression
De Ingeniis et al. (2012) reported that the 320-amino acid PYCR2 protein is 84% similar to PYCR1 (179035). Western blot analysis of fractionated Lu1205 human melanoma cells revealed that PYCR2 is a mitochondrial protein.

Nakayama et al. (2015) found expression of the PYCR2 gene in the developing human brain. Immunoblot analysis of HEK293 cells showed that the PRCR2 protein localized to the mitochondria.

Using a LacZ knockin reporter, Escande-Beillard et al. (2020) showed that Pycr2 was mainly expressed in cortex, hippocampus, corpus callosum, and cerebellum of mouse brain. Pycr2 was undetectable in midbrain structures.

▼ Gene Function
Proline can be synthesized beginning with glutamate or ornithine, and both pathways converge with the synthesis of the PYCR substrate P5C. Using Western blot analysis, De Ingeniis et al. (2012) found that Lu1205 cells had relatively high expression of PYCR1, PYCR2, and PYCRL (616408). Knockdown of PYCR1 and PYCR2 in Lu1205 cells via small interfering RNA reduced the ratio of proline to glutamate, indicating that PYCR1 and PYCR2 both contribute to biosynthesis of proline from glutamate. In contrast, knockdown of PYCRL decreased the ratio of proline to ornithine, indicating that PYCRL is involved in the ornithine route of proline synthesis. PYCR1 showed a small contribution to proline synthesis via the ornithine route. De Ingeniis et al. (2012) concluded that PYCR2 is used exclusively for biosynthesis of proline from glutamate.

▼ Biochemical Features
Escande-Beillard et al. (2020) determined the crystal structure of the human PYCR2 apoenzyme at 3.4-angstrom resolution. The PYCR2 structure contained 5 dimers assembled into a decamer, with the C-terminal domains of PYCR2 driving most of the contacts to form the hollow cylindrical core of the decamer, and the N-terminal domains lining the periphery of the characteristic yoyo-like structure.

▼ Mapping
De Ingeniis et al. (2012) reported that the PYCR2 gene maps to chromosome 1q42.13.

▼ Molecular Genetics
In 4 children from 2 unrelated consanguineous families with hypomyelinating leukodystrophy-10 (HLD10; 616420), Nakayama et al. (2015) identified 2 homozygous missense mutations in the PYCR2 gene (R119C, 616406.0001 and R251C, 616406.0002), respectively. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. In vitro studies showed that the mutations resulted in decreased protein expression. Mutant cells and cells transfected with an engineered truncated PYCR2 variant showed decreased staining for a mitochondrial membrane-potential-dependent marker, suggesting that the gene plays a role in maintaining mitochondrial membrane potential. Loss of PYCR2 resulted in increased susceptibility to apoptosis under oxidative stress. Pathogenic variants in the PYCR2 gene were not found in the exomes from 82 additional individuals with microcephaly.

In 14 patients from 11 families, 10 of which were consanguineous, with HLD10, Zaki et al. (2016) identified 6 different homozygous mutations in the PYCR2 gene (see, e.g., 616406.0003-616406.0006). Ten of the families were Egyptian and 1 was Pakistani. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 4 missense mutations, 1 truncating mutation, and 1 splice site mutation. In vitro functional studies of selected mutations showed that they impaired protein dimerization, putatively resulting in a loss of function.

▼ Animal Model
Nakayama et al. (2015) found that morpholino knockdown of 1 of the 2 PYCR2 zebrafish orthologs, pycr1b, resulted in a small head and eyes, short body, down-tilted tail, and hypomotility. The effects were dose-dependent. The microcephaly phenotype could be rescued by wildtype PYCR2 transcripts.

Escande-Beillard et al. (2020) found that Pycr2 -/- mice were normal at birth, but that they rapidly displayed symptoms of neurodegeneration, phenocopying human HLD10. Loss of Pycr2 significantly altered general brain architecture in mice, leading to axonopathy, hypomyelination, and death of cells from neuronal and oligodendroglial lineages. In addition, deletion of Pycr2 resulted in loss of endogenous Pycr1 in the neurons of Pycr2 -/- mice. In vitro analysis with primary neural stem cells (NSCs) showed that Pycr2 was not necessary for maintenance or multilineage potency of undifferentiated NSCs but was essential for neuronal survival and oligodendrocyte maturation. Further analysis revealed that loss of PYCR2 increased the cerebral glycine levels in both mice and humans by upregulating expression of SHMT2 (138450). Shmt2 knockdown in Pycr2 -/- neurons normalized glycine levels and partially rescued neuronal defects.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, ARG119CYS
In 2 sibs, born of consanguineous Omani parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Nakayama et al. (2015) identified a homozygous c.355C-T transition (c.355C-T, NM_013328.3) in the PYCR2 gene, resulting in an arg119-to-cys (R119C) substitution at a conserved residue in the NADH-binding domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was filtered against the dbSNP (build 134-137), Exome Variant Server, and 1000 Genomes Project databases. Patient-derived lymphoblastoid cells and HEK293 cells transfected with the R119C mutation showed a marked decrease in levels of the mutant protein, which localized properly to the mitochondria. Cells transfected with the mutation showed increased apoptosis in response to oxidative stress compared to wildtype. The mutant transcript was unable to rescue the microcephaly phenotype of a zebrafish knockout.

.0002 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, ARG251CYS
In 2 sisters, born of consanguineous Palestinian parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Nakayama et al. (2015) identified a homozygous c.751C-T transition (c.751C-T, NM_013328.3) in the PYCR2 gene, resulting in an arg251-to-cys (R251C) substitution at a conserved residue in the dimerization domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. The mutation was filtered against the dbSNP (build 134-137), Exome Variant Server, and 1000 Genomes Project databases. HEK293 cells transfected with the R251C mutation showed a small decrease in levels of the mutant protein, which localized properly to the mitochondria. Coimmunoprecipitation assays showed that the R251C variant decreased but did not completely abolish the ability of PYCR2 to form a homodimer. Cells transfected with the mutation showed increased apoptosis in response to oxidative stress compared to wildtype. The mutant transcript was unable to rescue the microcephaly phenotype of a zebrafish knockout.

.0003 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, ARG266TER
In 6 children from 5 unrelated Egyptian families with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.796G-A transition (chr1.226,108,909G-A, GRCh37) in the PYCR2 gene, resulting in an arg266-to-ter (R266X) substitution in the dimerization domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, 4 of which were consanguineous. The variant was filtered against the ExAC database and an in-house exome database of 5,000 individuals. Western blot analysis of 1 patient's fibroblasts showed absence of the protein, consistent with a complete loss of function.

.0004 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, ARG199TRP
In 2 unrelated children, born of consanguineous Egyptian parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.595G-A transition in the PYCR2 gene, resulting in an arg199-to-trp (R199W) substitution at a highly conserved residue in the dimerization domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutations were filtered against the ExAC database and an in-house exome database of 5,000 individuals. One patient had 2 older deceased sibs with a similar disorder. In vitro functional expression studies showed that the mutant protein had reduced coprecipitation with the wildtype protein compared to controls, suggesting that the mutation impaired protein multimerization.

.0005 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, CYS232GLY
In a patient, born of consanguineous Egyptian parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.694A-C transversion in the PYCR2 gene, resulting in a cys232-to-gly (C232G) substitution at a highly conserved residue in the dimerization domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the ExAC database and an in-house exome database of 5,000 individuals. The patient had 2 older deceased sibs with a similar disorder. In vitro functional expression studies showed that the mutant protein had reduced coprecipitation with the wildtype protein compared to controls, suggesting that the mutation impaired protein multimerization.

.0006 LEUKODYSTROPHY, HYPOMYELINATING, 10
PYCR2, VAL184ALA
In 2 sibs, born of consanguineous Egyptian parents, with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.773T-C transition in the PYCR2 gene, resulting in a val184-to-ala (V184A) substitution at a highly conserved residue in the dimerization domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, and segregated with the disorder in the family. The variant was filtered against the ExAC database and an in-house exome database of 5,000 individuals. Functional studies of the variant and studies of patient cells were not performed.

Tags: 1q42.12

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