Abnormal development of hypoxanthine–guanine phosphoribosyltransferase-deficient CNS neuroblastoma

Connolly, G.P.; Duley, JA; Stacey, N C

doi:10.1016/s0006-8993(01)02909-2

Cited by 18 publications

(11 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HPRT-deficient dopamine neuronlike lines show a loss of dopamine content that is analogous to that reported for the LND brain (Bitler and Howard, 1986;Yeh et al, 1998;Lewers et al, 2008). These models also reveal changes in neuronal microstructure in the form of abnormal numbers or morphology of neurites, which are comparable to dendrites or axons in vivo (Stacey et al, 1999;Connolly et al, 2001;Shirley et al, 2007).…”

Section: Tissue Culture Models: Neural and Non-neuralmentioning

confidence: 62%

Lesch-Nyhan disease: from mechanism to model and back again

Jinnah

2009

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Lesch-Nyhan disease (LND) is a rare inherited disorder caused by mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by overproduction of uric acid, leading to gouty arthritis and nephrolithiasis. Affected patients also have characteristic neurological and behavioral anomalies. Multiple cell models have been developed to study the molecular and metabolic aspects of LND, and several animal models have been developed to elucidate the basis for the neurobehavioral syndrome. The models have different strengths and weaknesses rendering them suitable for studying different aspects of the disease. The extensive modeling efforts in LND have questioned the concept that an ‘ideal’ disease model is one that replicates all of its features because the pathogenesis of different elements of the disease involves different mechanisms. Instead, the modeling efforts have suggested a more fruitful approach that involves developing specific models, each tailored for addressing specific experimental questions.

show abstract

Section: Tissue Culture Models: Neural and Non-neuralmentioning

confidence: 62%

Lesch-Nyhan disease: from mechanism to model and back again

Jinnah

2009

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…To circumvent this cell type problem, researchers developed HPRTdeficient subclones of glioma and neuroblastoma cell lines [Shirley et al, 2007]. These neural models have allowed researchers to assess specific deficits in neurotransmitters [Bitler and Howard, 1986;Yeh et al, 1998;Lewers et al, 2008] and neuronal structure abnormalities [Connolly et al, 2001;Shirley et al, 2007] that occur when HPRT activity is absent. However, results obtained from these models may lose relevance, as the cells were obtained from nonpatient neuronal tumors.…”

Section: Tissue Culture Models Of Lnsmentioning

confidence: 99%

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

et al. 2016

View full text Add to dashboard Cite

Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by mutations in HPRT1, an important enzyme in the purine salvage pathway. Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in hypoxanthine and guanine recycling can lead to such a profound neurological phenotype. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients, though none have led to a satisfactory explanation of the disease. New technologies such as next-generation sequencing, optogenetics, genome editing, and induced pluripotent stem cells provide a unique opportunity to map the precise sequential pathways leading from genotype to phenotype.

show abstract

“…In addition, several HPRT‐deficient cell lines including primary human skin fibroblasts, immortalized mouse skin fibroblasts, mouse Neuro‐2a neuroblastoma cells and rat B103 neuroblastoma are used as biochemical models for LND (Zoref‐Shani et al . 1993; Connolly et al . 2001; Fairbanks et al .…”

mentioning

confidence: 99%

Decreased GTP‐stimulated adenylyl cyclase activity in HPRT‐deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes

Pinto¹,

Seifert²

2005

Journal of Neurochemistry

View full text Add to dashboard Cite

Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support G s -protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT -membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.

show abstract

Abnormal development of hypoxanthine–guanine phosphoribosyltransferase-deficient CNS neuroblastoma

Cited by 18 publications

References 21 publications

Lesch-Nyhan disease: from mechanism to model and back again

Lesch-Nyhan disease: from mechanism to model and back again

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

Decreased GTP‐stimulated adenylyl cyclase activity in HPRT‐deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes

Contact Info

Product

Resources

About