Alternative titles; symbols
HGNC Approved Gene Symbol: PURA
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38) : 5:140,114,109-140,125,619 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties | 616158 | Autosomal dominant | 3 |
The PURA gene encodes a highly conserved protein with regulatory roles in DNA replication, gene transcription, RNA transport, and mRNA translation (summary by Hunt et al., 2014). PURA is essential for normal brain development, synapse formation, and proliferation of neurons, oligodendrocytes, and astrocytes in the central nervous system (summary by Tanaka et al., 2015).
Bergemann and Johnson (1992) characterized an approximately 28-kD protein from HeLa cell nuclear extracts that bound specifically to a purine-rich repeat element located at a site of DNA binding upstream of the human c-myc gene, and at origins of replication and transcription initiation sites in a variety of eukaryotes. Bergemann et al. (1992) cloned and sequenced the cDNA encoding this protein, designated PURA, from a human fetal liver cDNA library. The deduced 322-amino acid protein contains an N-terminal glycine-rich region, 3 repeats of a 23-amino acid class I motif, 2 repeats of a 26-amino acid class II motif, an amphipathic helix, and a C-terminal glutamine-glutamate-rich domain. Northern blot analysis of human fetal liver, HeLa cells, lung tumor cells, and hepatoma cells showed expression of 4 transcripts, from 2.0 to 5.0 kb, that are either multiple PURA transcripts or homologous mRNAs. RACE-PCR suggested the presence of 3 PURA transcripts of 1.6 to 2.1 kb.
Kelm et al. (1997) cloned mouse Pura (p46) and Purb (p44) and identified them as the 2 components of the previously designated vascular actin single-stranded DNA-binding factor-2, which specifically bound to purine-rich regions within an enhancer and an exon of vascular actin (Kelm et al., 1996).
Bergemann et al. (1992) used gel shift assays to show that PURA binds preferentially to single-stranded DNA containing the purine-rich element.
Pur-alpha is a single-stranded DNA-binding protein with specific affinity for a purine-rich element of the configuration (GGN)n present in several initiation zones of eukaryotic DNA replication. It interacts with large T-antigen and cellular protein YB-1 (154030) to activate JC viral DNA transcription in human cells (Chen et al., 1995). The functional activities of Pur-alpha, together with its evolutionary conservation, suggested that it may represent an important link between DNA replication and differential gene expression.
Gallia et al. (2000) reviewed the structure and function of PURA. The central repeat region of PURA mediates binding to its single-stranded DNA target sequence as well as to regulatory proteins, both of which are modulated by RNA. In its C-terminal half, PURA contains an amphipathic alpha-helix with limited homology to the large tumor antigen of several polyomaviruses with a PSYC, or 'psycho,' motif. It also contains an N-terminal glycine-rich region. PURA is implicated in the transcriptional control of a number of cellular genes, including MBP (159430), FE65 (APBB1; 602709), and neuronal ACHR (e.g., CHRNB2; 118507), as well as viral promoters for JCV and HIV-1, which replicate in the central nervous system. PURA is also involved in the control of cell growth and interacts with the hypophosphorylated form of RB1 (614041).
Fragile X-associated tremor/ataxia syndrome (FXTAS; 300623) is a neurodegenerative disorder caused by FMR1 premutation alleles containing 55 to 200 repeats of the trinucleotide CGG (309550.0004). Using gel-shift assays with mouse and fly brain lysates, followed by protein purification and mass spectroscopy, Jin et al. (2007) showed that Pur-alpha bound (CGG)105. Pur-alpha bound CGG repeats in a sequence-specific manner, and overexpression of Pur-alpha in a Drosophila model of FXTAS suppressed CGG repeat-mediated neurodegeneration in a dose-dependent manner. Furthermore, immunohistochemical analysis showed that Pur-alpha was ubiquitously expressed in wildtype fly eyes, but it was sequestered in inclusions in fly eyes expressing (CGG)105. Human PURA was present in ubiquitin-positive inclusions in postmortem FXTAS brain tissues. Jin et al. (2007) hypothesized that PURA is sequestered from its normal function by binding premutation CGG repeats, leading to pathologic changes in FXTAS.
Using a 16-kb genomic probe together with hybridization of a cDNA probe to blots of DNA from human/hamster cell lines, Ma et al. (1995) mapped the PURA gene to 5q31. This region is frequently deleted in myelogenous leukemias in hematologic malignancies and other cancers. Sequences with homology to the PURA gene were also present at 6q14.
Lalani et al. (2014) identified de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0001-600473.0005) in 11 (0.52%) of 2,117 pediatric patients with various neurodevelopmental disorders who underwent whole-exome sequencing. The patients with PURA mutations had a similar neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158). There were 4 truncating mutations, 5 missense mutations, and 2 in-frame deletions. Functional studies of the variants were not performed, but the presence of truncating mutations suggested at least a partial loss of protein function as responsible for the phenotype.
In 4 unrelated girls with NEDRIHF, Hunt et al. (2014) identified 4 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0006-600473.0008). Two mutations were truncating frameshifts, 1 was missense, and 1 was an in-frame deletion. The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.
The Deciphering Developmental Disorders Study (2015) reported 3 patients with a neurodevelopmental disorder who had de novo heterozygous mutations in the PURA gene. In 2 of these patients, the mutation was a frameshift; in the third it was missense.
In 6 unrelated children with NEDRIHF, Tanaka et al. (2015) identified 6 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0008-600473.0010). The mutations, which were found by whole-exome sequencing, comprised missense, frameshift, and small intragenic deletions. Functional studies of the variants were not performed.
Reijnders et al. (2018) reported 32 unrelated patients with NEDRIHF associated with de novo heterozygous mutations in the PURA gene. Most patients were identified through whole-exome sequencing in a research or clinical setting. There were missense, small deletions, and frameshift mutations that occurred throughout the gene. All missense variants occurred in a PUR repeat domain. Although several mutations were recurrent (see, e.g., K97E, 600473.0004; F271del, 600473.0001; and F233del; 600473.0008), patients with the same mutations showed remarkable phenotypic variability. Functional studies of the variants and studies of patient cells were not performed. However, using molecular modeling, the authors classified the mutations according to their predicted effects on domain folding and protein function. Overall, there were no genotype/phenotype correlations.
Khalili et al. (2003) found that Pura -/- mice appeared normal at birth, but at 2 weeks of age, they developed neurologic problems characterized by severe tremor and spontaneous seizures, and they died by 4 weeks. Regions of the hippocampus and cerebellum of Pura -/- mice showed severely lower numbers of neurons compared with wildtype littermates, and lamination of these regions was aberrant at time of death. Immunohistochemical analysis of Mcm7 (600592), a marker for DNA replication, revealed lack of proliferation of precursor cells in these regions in Pura -/- mice. Proliferation was also low or absent in several other tissues of Pura -/- mice, including those of myeloid lineage, whereas those of Pura +/- mice were intermediate. Evaluation of brain sections indicated reduced myelination and pathologic development of oligodendrocytes and astrocytes. At postnatal day 5, a critical time for cerebellar development, Pura and Cdk5 (123831) were both at peak levels in bodies and dendrites of Purkinje cells of wildtype mice, but both proteins were absent in dendrites of Pura -/- mice. Immunohistochemical analysis revealed dramatic reduction in both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Khalili et al. (2003) concluded that PURA has a role in developmentally timed DNA replication in specific cell types.
Lalani et al. (2014) found that mutant Caenorhabditis elegans animals homozygous for a null allele of the PURA ortholog plp-1 were sterile and had defective locomotion compared to wildtype, suggesting a role for PURA in both germline and somatic neuronal tissues.
In a 6-month-old boy with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Lalani et al. (2014) identified a de novo heterozygous 3-bp in-frame deletion (c.812_814delTCT) in the PURA gene, resulting in the deletion of the conserved residue phe271 (Phe271del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 134), 1000 Genomes Project, or Exome Variant Server databases or in the exomes of about 6,000 control individuals. Functional studies of the variant were not performed.
In a 7-month-old boy with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Lalani et al. (2014) identified a de novo heterozygous 2-bp deletion (c.307_308delTC) in the PURA gene, resulting in a frameshift and premature termination (Ser103HisfsTer97). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 134), 1000 Genomes Project, or Exome Variant Server databases or in the exomes of about 6,000 control individuals. Functional studies of the variant were not performed, but the findings were consistent with at least a partial loss of function.
In a 10-month-old boy with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Lalani et al. (2014) identified a de novo heterozygous c.556C-T transition in the PURA gene, resulting in a gln186-to-ter (Q186X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 134), 1000 Genomes Project, or Exome Variant Server databases or in the exomes of about 6,000 control individuals. Functional studies of the variant were not performed, but the findings were consistent with at least a partial loss of function.
In a 21-month-old girl with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Lalani et al. (2014) identified a de novo heterozygous c.289A-G transition in the PURA gene, resulting in a lys97-to-glu (K97E) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 134), 1000 Genomes Project, or Exome Variant Server databases or in the exomes of about 6,000 control individuals. Functional studies of the variant were not performed.
In a 23-month-old girl with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Lalani et al. (2014) identified a de novo heterozygous c.299T-C transition in the PURA gene, resulting in a leu100-to-pro (L100P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 134), 1000 Genomes Project, or Exome Variant Server databases or in the exomes of about 6,000 control individuals. Functional studies of the variant were not performed.
In a 4-year-old girl (patient 1) with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Hunt et al. (2014) identified a de novo heterozygous 2-bp deletion (c.726_727delGT, NM_005859.4) in the PURA gene, resulting in a frameshift and premature termination (Phe243TyrfsTer50) in the Pur repeat III domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. Hunt et al. (2014) noted that since the PURA gene contains only 1 exon, the mutation would not lead to nonsense-mediated mRNA decay.
In a 12-year-old girl (patient 3) with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Hunt et al. (2014) identified a de novo heterozygous c.616A-T transversion (c.616A-T, NM_005859.4) in the PURA gene, resulting in an ile206-to-phe (I206F) substitution at a highly conserved residue in the Pur repeat II domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.
In a 6-year-old girl (patient 4) with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Hunt et al. (2014) identified a de novo heterozygous 3-bp deletion (c.697_699delTTC, NM_005859.4), resulting in the deletion of a highly conserved residue (Phe233del) in the Pur repeat III domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.
Tanaka et al. (2015) identified a de novo heterozygous c.697_699delTTC mutation in a 6-month-old girl with NEDRIHF. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variant were not performed.
In an 8-year-old boy with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Tanaka et al. (2015) identified a de novo heterozygous c.563T-C transition in the PURA gene, resulting in an ile188-to-thr (I188T) substitution at a highly conserved residue in the PUR repeat II domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variant were not performed.
In a 5-year-old girl with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Tanaka et al. (2015) identified a de novo heterozygous 9-bp deletion in the PURA gene (c.302_310del), resulting in an in-frame deletion of 3 conserved residues (Thr101_Ser103del) in the PUR repeat I domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variant were not performed.
Bergemann, A. D., Johnson, E. M. The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication. Molec. Cell. Biol. 12: 1257-1265, 1992. [PubMed: 1545807] [Full Text: https://doi.org/10.1128/mcb.12.3.1257-1265.1992]
Bergemann, A. D., Ma, Z.-W., Johnson, E. M. Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein. Molec. Cell. Biol. 12: 5673-5682, 1992. [PubMed: 1448097] [Full Text: https://doi.org/10.1128/mcb.12.12.5673-5682.1992]
Chen, N. N., Chang, C.-F., Gallia, G. L., Kerr, D. A., Johnson, E. M., Krachmarov, C. P., Barr, S. M., Frisque, R. J., Bollag, B., Khalili, K. Cooperative action of cellular proteins YB-1 and Pur-alpha with the tumor antigen of the human JC polyomavirus determines their interaction with the viral lytic control element. Proc. Nat. Acad. Sci. 92: 1087-1091, 1995. [PubMed: 7862639] [Full Text: https://doi.org/10.1073/pnas.92.4.1087]
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223-228, 2015. [PubMed: 25533962] [Full Text: https://doi.org/10.1038/nature14135]
Gallia, G. L., Johnson, E. M., Khalili, K. Pur-alpha: a multifunctional single-stranded DNA- and RNA-binding protein. Nucleic Acids Res. 28: 3197-3205, 2000. [PubMed: 10954586] [Full Text: https://doi.org/10.1093/nar/28.17.3197]
Hunt, D., Leventer, R. J., Simons, C., Taft, R., Swoboda, K. J., Gawne-Cain, M., the DDD study, Magee, A. C., Turnpenny, P. D., Baralle, D. Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J. Med. Genet. 51: 806-813, 2014. [PubMed: 25342064] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102798]
Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T. C., Liu, H., Feng, Y., Warren, S. T. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55: 556-564, 2007. [PubMed: 17698009] [Full Text: https://doi.org/10.1016/j.neuron.2007.07.020]
Kelm, R. J., Jr., Elder, P. K., Strauch, A. R., Getz, M. J. Sequence of cDNAs encoding components of vascular actin single-stranded DNA-binding factor 2 establish identity to Pur-alpha and Pur-beta. J. Biol. Chem. 272: 26727-26733, 1997. [PubMed: 9334258] [Full Text: https://doi.org/10.1074/jbc.272.42.26727]
Kelm, R. J., Jr., Sun, S., Strauch, A. R., Getz, M. J. Repression of transcriptional enhancer factor-1 and activator protein-1-dependent enhancer activity by vascular actin single-stranded DNA binding factor 2. J. Biol. Chem. 271: 24278-24285, 1996. [PubMed: 8798674] [Full Text: https://doi.org/10.1074/jbc.271.39.24278]
Khalili, K., Del Valle, L., Muralidharan, V., Gault, W. J., Darbinian, N., Otte, J., Meier, E., Johnson, E. M., Daniel, D. C., Kinoshita, Y., Amini, S., Gordon, J. Pur-alpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Molec. Cell. Biol. 23: 6857-6875, 2003. [PubMed: 12972605] [Full Text: https://doi.org/10.1128/MCB.23.19.6857-6875.2003]
Lalani, S. R., Zhang, J., Schaaf, C. P., Brown, C. W., Magoulas, P., Tsai, A. C.-H., El-Gharbawy, A., Wierenga, K. J., Bartholomew, D., Fong, C.-T., Barbaro-Dieber, T., Kukolich, M. K., and 26 others. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am. J. Hum. Genet. 95: 579-583, 2014. [PubMed: 25439098] [Full Text: https://doi.org/10.1016/j.ajhg.2014.09.014]
Ma, Z.-W., Pejovic, T., Najfeld, V., Ward, D. C., Johnson, E. M. Localization of PURA, the gene encoding the sequence-specific single-stranded-DNA-binding protein Pur-alpha, to chromosome band 5q31. Cytogenet. Cell Genet. 71: 64-67, 1995. [PubMed: 7606931] [Full Text: https://doi.org/10.1159/000134065]
Reijnders, M. R. F., Janowski, R., Alvi, M., Self, J. E., van Essen, T. J., Vreeburg, M., Rouhl, R. P. W., Stevens, S. J. C., Stegmann, A. P. A., Schieving, J., Pfundt, R., van Dijk, K., and 41 others. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. J. Med. Genet. 55: 104-113, 2018. [PubMed: 29097605] [Full Text: https://doi.org/10.1136/jmedgenet-2017-104946]
Tanaka, A. J., Bai, R., Cho, M. T., Anyane-Yeboa, K., Ahimaz, P., Wilson, A. L., Kendall, F., Hay, B., Moss, T., Nardini, M., Bauer, M., Retterer, K., Juusola, J., Chung, W. K. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harbor Molec. Case Stud. 1: a000356, 2015. Note: Electronic Article. [PubMed: 27148565] [Full Text: https://doi.org/10.1101/mcs.a000356]