Alternative titles; symbols
HGNC Approved Gene Symbol: PYCR1
SNOMEDCT: 778068007;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,932,391-81,937,300 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Cutis laxa, autosomal recessive, type IIB | 612940 | Autosomal recessive | 3 |
| Cutis laxa, autosomal recessive, type IIIB | 614438 | Autosomal recessive | 3 |
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).
Dougherty et al. (1992) cloned a cDNA by complementation of proline auxotrophy in a Saccharomyces cerevisiae mutant strain ('pro3'). The 1,810-bp cDNA hybridized to a 1.85-kb mRNA in samples from human cell lines and predicated a 319-amino acid, 33.4-kD protein.
De Ingeniis et al. (2012) reported that the 319-amino acid PYCR1 protein is 84% similar to PYCR2 (616406). Western blot analysis of fractionated Lu1205 human melanoma cells revealed that PYCR1 is a mitochondrial protein.
By somatic cell hybridization, Dougherty et al. (1992) mapped the PYCR1 gene to chromosome 17. De Ingeniis et al. (2012) reported that the PYCR1 gene maps to chromosome 17q25.3.
Merrill et al. (1989) studied the properties of human erythrocyte pyrroline-5-carboxylate reductase. They concluded that in addition to the traditional role of catalyzing the obligatory and final unidirectional step in pyrroline biosynthesis, the enzyme may play a physiologic role in the generation of NADP(+) in some cell types including human erythrocytes.
Reversade et al. (2009) reported that the PYCR1 protein colocalized with various mitochondrial markers, including delta-1-pyrroline-5-carboxylate synthetase (P5CS; 138250), which also belongs to the proline metabolic pathway. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase in apoptosis.
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 PYCR1 is used primarily for biosynthesis of proline from glutamate.
Loayza-Puch et al. (2016) harnessed ribosome profiling for sensing restrictive amino acids and developed diricore, a procedure for differential ribosome measurements of codon reading. They first demonstrated the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L-asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS; 108370). Loayza-Puch et al. (2016) then applied diricore to kidney cancer and discovered signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production, suggesting a compensatory mechanism allowing tumor expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumor, the authors also uncovered signals indicating restrictive proline and showed that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system.
Autosomal Recessive Cutis Laxa Type IIB
In affected members of 2 Maritime Canadian families of French Acadian descent with autosomal recessive cutis laxa type IIB (ARCL2B; 612940), Guernsey et al. (2009) identified a homozygous mutation in the PYCR1 gene (179035.0001), resulting in loss of protein function.
In consanguineous families segregating autosomal recessive cutis laxa, including families previously reported by Al-Gazali et al. (2001), Hamamy et al. (2005), Nanda et al. (2008), and Rajab et al. (2008), Reversade et al. (2009) identified homozygosity or compound heterozygosity for mutations in the PYCR1 gene (see, e.g., 179035.0002-179035.0008).
Autosomal Recessive Cutis Laxa Type IIIB
In 2 families diagnosed with de Barsy syndrome (ARCL3B; 614438) by Kunze et al. (1985), Reversade et al. (2009) identified homozygosity for mutations in the PYCR1 gene (179035.0009, 179035.0010).
Lin et al. (2011) identified compound heterozygosity for a frameshift and missense mutation in the PYCR1 gene in a patient with de Barsy syndrome (179035.0011, 179035.0012).
In affected members of 2 Maritime Canadian families of French Acadian descent with autosomal recessive cutis laxa type IIB (ARCL2B; 612940), Guernsey et al. (2009) identified a homozygous 797G-A transition in the last amino acid encoded by exon 6 of the PYCR1 gene, resulting in an arg266-to-gln (R266Q) substitution. Studies of RNA from patients' blood lymphocytes indicated that the mutation affected the exon 6 donor splice site, resulting in the skipping of exon 6 and deletion of 54 amino acids of the PYCR1 protein, including the conserved reductase signature. The mutation also generated an obligatory frameshift in the downstream exons, leading to premature termination. The findings suggested that loss of PYCR1 function is responsible for the phenotype. The mutation was not found in 96 controls, but was found in heterozygosity in 1 of 142 Maritime population control samples, consistent with a founder effect in this population. The phenotype was characterized by lax, wrinkled skin with reduced elasticity, lax joints, and mild craniofacial dysmorphic features. There were no metabolic abnormalities.
In a Palestinian girl with intrauterine growth retardation, cutis laxa, agenesis of the corpus callosum, mental retardation, and athetoid movements (ARCL2B; 612940), previously described by Hamamy et al. (2005), Reversade et al. (2009) identified homozygosity for a 616G-T transversion in exon 5 of the PYCR1 gene, resulting in a gly206-to-trp (G206W) substitution. Analysis of skin fibroblasts revealed a reduction in protein abundance relative to control cells.
In 3 Palestinian sibs with intrauterine growth retardation, cutis laxa, hip dislocation, osteopenia, mild abnormalities of the corpus callosum, and mild mental retardation (ARCL2B; 612940), born of first-cousin parents and previously reported by Al-Gazali et al. (2001), Reversade et al. (2009) identified homozygosity for a 22-bp deletion (617_633+6del) encompassing the exon-intron boundary of exon 5 of the PYCR1 gene.
In 3 children with intrauterine growth retardation, cutis laxa, hip dislocation, hernias, osteopenia, and mental retardation (ARCL2B; 612940) from 2 unrelated consanguineous Kuwaiti families, originally reported by Nanda et al. (2008), Reversade et al. (2009) identified homozygosity for a 797G-A transition in exon 6 of the PYCR1 gene, resulting in an arg266-to-gln (R266Q) substitution predicted to affect splicing by altering the invariable donor splice site at the 3-prime end of exon 6.
In affected members of a Jordanian family with intrauterine growth retardation, cutis laxa, hernias, abnormal corpus callosum, and mental retardation (ARCL2B; 612940), and a Syrian patient with intrauterine growth retardation, cutis laxa, hernias, osteopenia, agenesis of the corpus callosum, and mental retardation who was previously reported by Al-Gazali et al. (2001), Reversade et al. (2009) identified homozygosity for a splice site deletion (797+2_797+5del) in intron 6 of the PYCR1 gene, predicted to result in K215_D319del. Analysis of skin fibroblasts from 1 of the affected Jordanian individuals revealed strongly reduced PYCR1 protein levels.
In an Italian patient with intrauterine growth retardation, congenital cutis laxa, hernias, osteopenia, and mental retardation (ARCL2B; 612940), Reversade et al. (2009) identified compound heterozygosity for a 1-bp deletion (11delG) in exon 1 of the PYCR1 gene, resulting in a frameshift and premature termination codon, and a 355C-G transversion in exon 4, resulting in an arg119-to-gly (R119G; 179035.0007) substitution. Analysis of skin fibroblasts from the patient revealed strongly reduced PYCR1 protein levels.
For discussion of the arg119-to-gly (R119G) mutation in the PYCR1 gene that was found in compound heterozygous state in a patient with intrauterine growth retardation, congenital cutis laxa, hernias, osteopenia, and mental retardation (ARCL2B; 612940) by Reversade et al. (2009), see 179035.0006.
In 3 sibs from a consanguineous Omani family with congenital cutis laxa, bowing of the long bones, multiple fractures due to osteopenia, and mental retardation (ARCL2B; 612940), originally reported by Rajab et al. (2008), Reversade et al. (2009) identified homozygosity for a 356G-A transition in exon 4 of the PYCR1 gene, resulting in an arg119-to-his (R119H) substitution.
In a patient from the U.S. with intrauterine growth retardation, cutis laxa, hip dislocation, hernias, abnormal corpus callosum, mental retardation, and cataract who was diagnosed with de Barsy syndrome (ARCL3B; 614438), Reversade et al. (2009) identified homozygosity for a 752G-A transition in exon 6 of the PYCR1 gene, resulting in an arg251-to-his (R251H) substitution. Analysis of skin fibroblasts revealed a reduction in protein abundance relative to control cells.
In 3 sibs from an Australian family with autosomal recessive cutis laxa and cataract, diagnosed with de Barsy syndrome (ARCL3B; 614438) by Kunze et al. (1985), Reversade et al. (2009) identified homozygosity for a 769G-A transition in exon 6 of the PYCR1 gene, resulting in an ala257-to-thr (A257T) substitution.
In a patient with de Barsy syndrome (ARCL3B; 614438), born to nonconsanguineous Chinese parents, Lin et al. (2011) identified compound heterozygous mutations in the PYCR1 gene: from his father, he inherited a 345delC mutation in exon 4 of the PYCR1 gene that resulted in a frameshift and premature termination (Pro115fsTer7); from his mother, he inherited a missense mutation (G248E; 179035.0012).
In a patient with de Barsy syndrome (ARCL3B; 614438), Lin et al. (2011) identified compound heterozygous mutations in the PYCR1 gene: a frameshift mutation inherited from his father (179035.0011), and 2 mutations in cis, 743G-A and 889G-A, in exon 6 and 8, respectively, inherited from his mother. The exon 8 transition resulted in a gly248-to-glu (G248E) substitution which, since gly248 was highly conserved across multiple species examined, was deemed to be the disease-associated mutation.
Al-Gazali, L. I., Sztriha, L., Skaff, F., Haas, D. Gerodermia osteodysplastica and wrinkly skin syndrome: are they the same? Am. J. Med. Genet. 101: 213-220, 2001. [PubMed: 11424136] [Full Text: https://doi.org/10.1002/ajmg.1352]
De Ingeniis, J., Ratnikov, B., Richardson, A. D., Scott, D. A., Aza-Blanc, P., De, S. K., Kazanov, M., Pellecchia, M., Ronai, Z., Osterman, A. L., Smith, J. W. Functional specialization in proline biosynthesis of melanoma. PLoS One 7: e45190, 2012. Note: Electronic Article. [PubMed: 23024808] [Full Text: https://doi.org/10.1371/journal.pone.0045190]
Dougherty, K. M., Brandriss, M. C., Valle, D. Cloning human pyrroline-5-carboxylate reductase cDNA by complementation in Saccharomyces cerevisiae. J. Biol. Chem. 267: 871-875, 1992. [PubMed: 1730675]
Guernsey, D. L., Jiang, H., Evans, S. C., Ferguson, M., Matsuoka, M., Nightingale, M., Rideout, A. L., Provost, S., Bedard, K., Orr, A., Dube, M.-P., Ludman, M., Samuels, M. E. Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. Am. J. Hum. Genet. 85: 120-129, 2009. [PubMed: 19576563] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.008]
Hamamy, H., Masri, A., Ajlouni, K. Wrinkly skin syndrome. Clin. Exp. Derm. 30: 590-592, 2005. [PubMed: 16045708] [Full Text: https://doi.org/10.1111/j.1365-2230.2005.01825.x]
Kunze, J., Majewski, F., Montgomery, P., Hockey, A., Karkut, I., Riebel, T. De Barsy syndrome--an autosomal recessive, progeroid syndrome. Europ. J. Pediat. 144: 348-354, 1985. [PubMed: 4076251] [Full Text: https://doi.org/10.1007/BF00441776]
Lin, D.-S., Chang, J.-H., Liu, H.-L., Wei, C.-H., Yeung, C.-Y., Ho, C.-S., Shu, C.-H., Chiang, M.-F., Chuang, C.-K., Huang, Y.-W., Wu, T.-Y., Jian, Y.-R., Huang, Z.-D., Lin, S.-P. Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of de Barsy syndrome. Am. J. Med. Genet. 155A: 3095-3099, 2011. [PubMed: 22052856] [Full Text: https://doi.org/10.1002/ajmg.a.34326]
Loayza-Puch, F., Rooijers, K., Buil, L. C. M., Zijlstra, J., Oude Vrielink, J. F., Lopes, R., Ugalde, A. P., van Breugel, P., Hofland, I., Wesseling, J., van Tellingen, O., Bex, A., Agami, R. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature 530: 490-494, 2016. [PubMed: 26878238] [Full Text: https://doi.org/10.1038/nature16982]
Merrill, M. J., Yeh, G. C., Phang, J. M. Purified human erythrocyte pyrroline-5-carboxylate reductase: preferential oxidation of NADPH. J. Biol. Chem. 264: 9352-9358, 1989. [PubMed: 2722838]
Nanda, A., Alsaleh, Q. A., Al-Sabah, H., Marzouk, E. E., Salam, A. M. A., Nanda, M., Anim, J. T. Gerodermia osteodysplastica/wrinkly skin syndrome: report of three patients and brief review of the literature. Pediat. Derm. 25: 66-71, 2008. [PubMed: 18304158] [Full Text: https://doi.org/10.1111/j.1525-1470.2007.00586.x]
Rajab, A., Kornak, U., Budde, B. S., Hoffmann, K., Jaeken, J., Nurnberg, P., Mundlos, S. Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman. Am. J. Med. Genet. 146A: 965-976, 2008. [PubMed: 18348262] [Full Text: https://doi.org/10.1002/ajmg.a.32143]
Reversade, B., Escande-Beillard, N., Dimopoulou, A., Fischer, B., Chng, S. C., Li, Y., Shboul, M., Tham, P.-Y., Kayserili, H., Al-Gazali, L., Shahwan, M., Brancati, F., and 35 others. Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genet. 41: 1016-1021, 2009. Note: Erratum: Nature Genet. 54: 213 only, 2022. [PubMed: 19648921] [Full Text: https://doi.org/10.1038/ng.413]