RESUMEN
Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.
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Adenilosuccinato Liasa , Errores Innatos del Metabolismo de la Purina-Pirimidina , Adenilosuccinato Liasa/deficiencia , Adenilosuccinato Liasa/genética , Adenilosuccinato Liasa/metabolismo , Trastorno Autístico , Humanos , Inosina Monofosfato , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , PurinasRESUMEN
Neuroblastoma is a malignant tumor originating from the primitive neural crest. Circular RNA (circRNA) Kinesin Superfamily Protein 2A (circKIF2A, also known as hsa_circ_0129276) has been reported to be upregulated in neuroblastoma. However, the molecular mechanism of circKIF2A participated in neuroblastoma is poorly defined. We analyzed the expression levels of circKIF2A, microRNA-377-3p (miR-377-3p), and phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in neuroblastoma tissues and cell lines (SK-N-AS and LAN-6) and explored their roles. The expression levels of CircKIF2A and PRPS1 were increased and that of miR-377-3p were decreased in 21 neuroblastoma tissues and cells. Functionally, the silencing of circKIF2A inhibited cell proliferation, migration, invasion, and glycolysis, boosted apoptosis in neuroblastoma cells in vitro, and blocked the growth of subcutaneously transplanted tumors in nude mice. Mechanically, circKIF2A could work as a sponge of miR-377-3p to enhance PRPS1 expression. CircKIF2A knockdown impedes cell proliferation, metastasis, and glycolysis partly by regulating the miR-377-3p/PRPS1 axis, suggesting that targeting circKIF2A can be a feasible therapeutic strategy for neuroblastoma.
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MicroARNs , Neuroblastoma , ARN Circular , Ribosa-Fosfato Pirofosfoquinasa , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , Neuroblastoma/genética , ARN Circular/genética , Ribosa-Fosfato Pirofosfoquinasa/genéticaRESUMEN
Phosphoribosyl pyrophosphate synthetases (EC 2.7.6.1) are key enzymes in the biological synthesis of phosphoribosyl pyrophosphate and are involved in diverse developmental processes. In our previous study, the PRPS1 gene was discovered as a key disease-resistance candidate gene in yellow drum, Nibea albiflora, in response to the infection of Vibrio harveyi, through genome-wide association analysis. This study mainly focused on the characteristics and its roles in immune responses of the PRPS1 gene in yellow drum. In the present study, the NaPRPS1 gene was cloned from yellow drum, encoding a protein of 320 amino acids. Bioinformatic analysis showed that NaPRPS1 was highly conserved during evolution. Quantitative RT-PCR demonstrated that NaPRPS1 was highly expressed in the head-kidney and brain, and its transcription and translation were significantly activated by V. harveyi infection examined by RT-qPCR and immunohistochemistry analysis, respectively. Subcellular localization revealed that NaPRPS1 was localized in cytoplasm. In addition, semi-in vivo pull-down assay coupled with mass spectrometry identified myeloid differentiation factor 88 (MyD88) as an NaPRPS1-interacting patterner, and their interaction was further supported by reciprocal pull-down assay and co-immunoprecipitation. The inducible expression of MyD88 by V. harveyi suggested that the linker molecule MyD88 in innate immune response may play together with NaPRPS1 to coordinate the immune signaling in yellow drum in response to the pathogenic infection. We provide new insights into important functions of PRPS1, especially PRPS1 in the innate immunity of teleost fishes, which will benefit the development of marine fish aquaculture.
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Enfermedades de los Peces , Perciformes , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Vibrio , Animales , Enfermedades de los Peces/genética , Peces/genética , Estudio de Asociación del Genoma Completo , Inmunidad Innata/genética , Factor 88 de Diferenciación Mieloide/genética , Perciformes/genética , Fosforribosil Pirofosfato , Vibrio/fisiologíaRESUMEN
Patients with relapsed/refractory Burkitt's lymphoma (BL) have a dismal prognosis. Current research efforts aim to increase cure rates by identifying high-risk patients in need of more intensive or novel therapy. The 8q24 chromosomal translocation of the c-Myc gene, a main molecular marker of BL, is related to the metabolism by regulating phosphoribosyl pyrophosphate synthetase 2 (PRPS2). In our study, BL showed significant resistance to thiopurines. PRPS2 homologous isoenzyme, PRPS1, was demonstrated to play the main role in thiopurine resistance. c-Myc did not have direct effects on thiopurine resistance in BL for only driving PRPS2. PRPS1 wild type (WT) showed different resistance to 6-mercaptopurine (6-mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback. PRPS1 A190T mutant could dramatically increase thiopurine resistance in BL. The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non-Hodgkin's lymphoma in China (CCCG-B-NHL-2015 study) confirms the value of high-dose methotrexate (MTX) and cytarabine (ARA-C) in high-risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.
Asunto(s)
Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Resistencia a Antineoplásicos/genética , Mercaptopurina/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Células HEK293 , Humanos , Mercaptopurina/farmacología , Mutación/genética , Nucleótidos/metabolismo , Tetrahidrofolatos/farmacología , Tetrahidrofolatos/uso terapéuticoRESUMEN
X-linked Charcot-Marie-Tooth disease-5 (CMTX5) is a rare hereditary disorder caused by mutations in the gene for phosphoribosyl pyrophosphate synthetase-1 (PRPS1). We investigated a boy with a novel PRPS1 mutation (c.334G>C, p.V112L) via genetic, neuropathological and enzymatic tests. The proband was a 13-year-old boy with congenital non-syndromic sensorineural deafness. At 3 year old, he developed progressive distal weakness of all limbs with muscle atrophy of both hands and shanks. Nerve conduction study revealed the loss of sensory nerve action potentials, and slowing down of motor nerve conduction velocities with a decrease of amplitudes of compound motor action potentials. Visual evoked potentials and brainstem auditory evoked potentials were not bilaterally evocable. Sural biopsy proved the loss of myelinated nerve fibers, with axonal degeneration, regenerating clusters and onion bulbs. Enzymatically, PRPS1 activity was close to zero in the proband and mildly reduced in his mother, compared with controls. To our knowledge, this is the first report of CMTX5 in a Chinese population. The genetic finding has expanded the genotypic spectrum of PRPS1 mutations.
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Enfermedad de Charcot-Marie-Tooth/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Adolescente , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , MutaciónRESUMEN
Colorectal cancer (CRC) ranks as the most frequent carcinoma worldwide. CRC patients show strong prognostic differences and responses to treatment, and 20% have incurable metastatic disease at diagnosis. We considered it essential to investigate mechanisms that control cellular regulatory networks, such as the miRNA-mRNA interaction, known to be involved in cancer pathogenesis. We conducted a human miRNome analysis by TaqMan low density array, comparing CRC to normal colon tissue (NCT, and experimentally identified gene targets of miRNAs deregulated, by anti-correlation analysis, with the CRC whole-transcriptome profile obtained from RNASeq experiments. We identified an integrated signature of 20 deregulated miRNAs in CRC. Enrichment analyses of the gene targets controlled by these miRNAs brought to light 25 genes, members of pathways known to lead to cell growth and death (CCND1, NKD1, FZD3, MAD2L1, etc.), such as cell metabolism (ACSL6, PRPS1-2). A screening of prognosis-mediated miRNAs underlined that the overexpression of miR-224 promotes CRC metastasis, and is associated with high stage and poor survival. These findings suggest that the biology and progression of CRC depend on deregulation of multiple miRNAs that cause a complex dysfunction of cellular molecular networks. Our results have further established miRNA-mRNA interactions and defined multiple pathways involved in CRC pathogenesis.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Anciano , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genéticaRESUMEN
Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.
Asunto(s)
Genes Ligados a X , Mutación Missense , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Moleculares , Linaje , Fenotipo , Conformación Proteica , Ribosa-Fosfato Pirofosfoquinasa/química , Adulto JovenRESUMEN
Relapse-specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate-limiting purine biosynthesis enzyme, confer significant drug resistances to combination chemotherapy in acute lymphoblastic leukemia (ALL). It is of particular interest to identify drugs to overcome these resistances. In this study, we found that PRPS1 mutant ALL cells specifically showed more chemosensitivity to 5-Fluorouracil (5-FU) than control cells, attributed to increased apoptosis of PRPS1 mutant cells by 5-FU. Mechanistically, PRPS1 mutants increase the level of intracellular phosphoribosyl pyrophosphate (PRPP), which causes the apt conversion of 5-FU to FUMP and FUTP in Reh cells, to promote 5-FU-induced DNA damage and apoptosis. Our study not only provides mechanistic rationale for re-targeting drug resistant cells in ALL, but also implicates that ALL patients who harbor relapse-specific mutations of PRPS1 might benefit from 5-FU-based chemotherapy in clinical settings.
Asunto(s)
Fluorouracilo/farmacología , Fosforribosil Pirofosfato/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Ribosa-Fosfato Pirofosfoquinasa/genética , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Células Jurkat , Lentivirus/genética , Ratones , Fosforribosil Pirofosfato/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.
Asunto(s)
Ataxia/genética , Enfermedad de Charcot-Marie-Tooth/genética , Trastornos Sordoceguera/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación/genética , Ribosa-Fosfato Pirofosfoquinasa/deficiencia , Secuencia de Aminoácidos , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Humanos , Fenotipo , Ribosa-Fosfato Pirofosfoquinasa/genéticaRESUMEN
PRPS1 (phosphoribosyl pyrophosphate synthetase 1), which drives the nucleotide biosynthesis pathway, modulates a variety of functions by providing central building blocks and cofactors for cell homeostasis. As tumor cells often display abnormal nucleotide metabolism, dysregulated de-novo nucleotide synthesis has potential impacts in cancers. We now report that PRPS1 is specifically and highly expressed in chemoresistant (CR) cancer cells derived from cisplatin-resistant human breast cancer cell lines SK-BR-3 and MCF-7. The inhibition of PRPS1 activity in CR cells by genetic silencing reduces cell viability and increases apoptosis in vitro, both of which can be further potentiated by cisplatin treatment. Significantly, such down-regulation of PRPS1 in CR cells when administered to nude mice enhanced the survival of those animals, as demonstrated by decreased tumor growth. Knockdown of PRPSI may cause these effects by potently inducing autonomous activation of caspase-3 and inhibiting the proliferation in the engrafted CR tumors. As a result, cisplatin sensitivity in a xenograft model of CR cancer cells can be restored by the down-regulation of PRPS1. Thus, PRPS1 inhibition may afford a therapeutic approach to relapsed patients with breast cancer, resistant to chemotherapy.
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Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , ARN Interferente Pequeño/genética , Ribosa-Fosfato Pirofosfoquinasa/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Silenciador del Gen , Humanos , Ratones , Ratones SCID , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribosa-Fosfato Pirofosfoquinasa/genética , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.
Asunto(s)
Cara/anomalías , Mutación con Ganancia de Función , Hiperuricemia/congénito , Hiperuricemia/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Niño , Cara/patología , Humanos , Hiperuricemia/patología , Masculino , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Ribosa-Fosfato Pirofosfoquinasa/metabolismoRESUMEN
BACKGROUND: The symptoms of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency diseases have been reported to be alleviated by medication. In the present study, we report biochemical data that favor PRPS1 deficiency-related hearing loss as a potential target for pharmaceutical treatment. METHODS: We recruited 42 probands from subjects aged less than 15 years with a moderate degree of nonsyndromic autosomal-recessive or sporadic sensorineural hearing loss (SNHL) in at least one side. Molecular genetic testing, including targeted exome sequencing (TES) of 129 genes for deafness, and in silico prediction were performed. RESULTS: A strong candidate variant (p.A82P) of PRPS1 is co-segregated with SNHL in X-linked recessive inheritance from one Korean multiplex SNHL family. Subsequent measurement of in vitro enzymatic activities of PRPS1 from erythrocytes of affected and unaffected family members, as well as unrelated normal controls, confirmed a pathogenic role of this variant. In detail, compared to normal hearing controls (0.23-0.26 nmol/ml/h), the proband, the affected sibling and their normal hearing mother demonstrated a significantly decreased PRPS1 enzymatic activity (0.07, 0.03 and 0.11 nmol/ml/h, respectively). This novel loss-of-function mutation of PRPS1 (p.A82P) is the ninth and sixth most reported mutation in the world and in Asia, respectively. CONCLUSIONS: DFNX1 was found to account for approximately 2.4% (1/42) of moderate SNHL in a Korean pediatric population. Confirmation of PRPS1 activity deficiency and an audiologic phenotype that initially begins in a milder form of SNHL, as in our family, should indicate the need for rigorous genetic screening as early as possible.
Asunto(s)
Sordera/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pérdida Auditiva Sensorineural/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Secuencia de Bases , Estudios de Casos y Controles , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación , Linaje , República de Corea , Secuenciación del ExomaRESUMEN
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Evidences have suggested that CD133 is a marker for a subset of glioblastoma cancer stem cells. However, whether miRNA plays a critical role in CD133(+) GBM is poorly understood. Here, we identified that miR-154 was upregulated in CD133(+) GBM cell lines. Knockdown of miR-154 remarkably suppressed proliferation and migration of CD133(+) GBM cells. Further study found that PRPS1 was a direct target of miR-154 in CD133(+) GBM cells. Overexpression of PRPS1 exhibited similar effects as miR-154 knockdown in CD133(+) GBMs. Our study identified miR-154 as a previously unrecognized positive regulator of proliferation and migration in CD133(+) GBM cells and a potentially therapeutic target of GBMs. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Antígeno AC133/metabolismo , Carcinogénesis/genética , Regulación hacia Abajo/genética , Glioblastoma/genética , Glioblastoma/patología , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , MicroARNs/metabolismo , Células Madre Neoplásicas/patología , Ribosa-Fosfato Pirofosfoquinasa/genética , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Regulación hacia Arriba/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
CASE SUMMARY: The patient is a 42-year-old female who presented with a de novo missense variant in the PRPS1 gene. Her phenotype includes asymmetric retinal dystrophy with sensory esotropia, congenital sensorineural hearing loss, neuropathy, and severe tremors with recent-onset ataxia. This contributes a new presentation of ophthalmic and neurological findings to the literature.
RESUMEN
PURPOSE: This study describes how the diagnosis of Usher syndrome was revised to PRPS1-associated retinopathy and Charcot-Marie-Tooth disease type 5. CASE REPORT: A 38-year-old female with bilaterally subnormal vision and non-congenital hearing loss was initially diagnosed with Usher syndrome, based on finding variants in three genes (MYO7A, USH2A, and PCDH15), was re-evaluated at the inherited retinal disorders clinic. She had asymmetric retinopathy and right macular pseudocoloboma. She was also found to have myopathic facies, poor grip strength and atrophy of the calf muscles. Whole exome sequencing including variants in PRPS1 showed a variant (NM_002764.4:c.287 G > A; p.Arg96Gln), which was not detected by targeted Sanger sequencing of the DNA from her mother and sister. CONCLUSION: The constellation of asymmetric retinopathy and non-congenital hearing impairment should prompt the clinician to search for other diagnoses that may not be covered by an Usher syndrome next generation sequencing panel. Interpretation of genetic testing results should be correlated with a detailed clinical phenotype.
RESUMEN
Phospho-ribosyl-pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1. This enzyme generates phospho-ribosyl-pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways. Arts syndrome, or severe PRPS1 deficiency, is an X-linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age. Supplementation of the purine and NAD pathways outside of PRPP-dependent reactions is a logical approach and has been reported in a handful of patients, two with S-adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR). We present the clinical course of a fourth Arts syndrome patient who was started on therapy and review previously reported patients. All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted.
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Phosphoribosylpyrophosphate synthetase 1 (PRS-I) is an enzyme involved in nucleotide metabolism. Pathogenic variants in the PRPS1 are rare and PRS-I deficiency can manifest as three clinical syndromes: X-linked non-syndromic sensorineural deafness (DFN2), X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5) and Arts syndrome. We present a Slovenian patient with PRS-I enzyme deficiency due to a novel pathogenic variant - c.424G > A (p.Val142Ile) in the PRPS1 gene, who presented with gross motor impairment, severe sensorineural deafness, balance issues, ataxia, and frequent respiratory infections. In addition, we report the findings of a systemic literature review of all described male cases of Arts syndrome and CMTX5 as well as intermediate phenotypes. As already proposed by other authors, our results confirm PRS-I deficiency should be viewed as a phenotypic continuum rather than three separate syndromes because there are multiple reports of patients with an intermediary clinical presentation.
RESUMEN
Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is the first enzyme in the de novo purine nucleotide synthesis pathway and is essential for cell development. However, the effect of PRPS1 on melanoma proliferation and metastasis remains unclear. This study aimed to investigate the regulatory mechanism of PRPS1 in the malignant progression of melanoma. Here, we found PRPS1 was upregulated in melanoma and melanoma cells. In addition, our data indicated that PRPS1 could promote the proliferation and migration and invasion of melanoma both in vitro and in vivo. PRPS1 also could inhibit melanoma cell apoptosis. Furthermore, we found NRF2 is an upstream transcription factor of PRPS1 that drive malignant progression of melanoma.
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Melanoma , Ribosa-Fosfato Pirofosfoquinasa , Humanos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Nucleótidos de Purina , Ribosa-Fosfato Pirofosfoquinasa/genética , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Síndrome , Regulación hacia ArribaRESUMEN
The PRPS1 gene encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). The phenotypes associated with PRPS1 mutations include DFN2 (mild PRS-1 deficiency), X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) (moderate PRS-1 deficiency), Arts syndrome (severe PRS-1 deficiency), and PRS-1 superactivity1. CMTX5 is a very rare hereditary neuropathy characterized by deafness, optic atrophy, and polyneuropathy. We herein report a Japanese patient with CMTX5 who had a novel hemizygous mutation c.82 G>C in PRPS1. Despite showing a typical clinical picture, the decrease in enzyme activity measured in the patient's erythrocytes was milder than in previously reported cases.
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Enfermedad de Charcot-Marie-Tooth , Polineuropatías , Enfermedad de Charcot-Marie-Tooth/genética , Pérdida Auditiva Central , Humanos , Japón , Trastornos Musculares Atróficos , Mutación/genética , Atrofias Ópticas Hereditarias , Ribosa-Fosfato Pirofosfoquinasa/genéticaRESUMEN
Phosphoribosyl pyrophosphate synthetase-1 (PRPS-1; EC 2.7.6.1.) catalyzes the binding of phosphate-group to ribose 5-phosphate, forming the 5-phosphoribosyl-1-pyrophosphate, which is necessary for the salvage pathways of purine and pyrimidine, pyridine nucleotide cofactors - NAD and NADP, the amino acids histidine and tryptophan biosynthesis. We aimed to investigate the impact of the different effectors on the activity of PRPS-1, to check the activity of the enzyme in vitro in a wide range of pHs and investigate some structural essentials of the enzyme, isolated from brain and liver. Molecular docking analyses were used to delineate the essentials of PRPS-1 structure, to find out the existence of enzyme effectors. Previously created by us kit was used for determination of the activity of PRPS-1 based on the formation of the inorganic phosphates (λ = 700 nm, Cary 60, Agilent, USA). Effectors impact on the activity of PRPS-1 was evaluated. In silico results of the effectors were later proven by in vitro experiments. For the first time biochemical essentials, including the existence of the multiple pockets, involvement of the amino acids into the processes of interactions with the effectors, evolutional of the sequence conservation, tissue depended Vmax differences were identified.