Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions

a role for EPAC in Lesch-Nyhan syndrome

Ghiabe-Henri Guibinga, Fiona Murray, Nikki Barron, William Pandori, Gorjan Hrustanovic

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS.

Original languageEnglish
Pages (from-to)4502-15
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number22
DOIs
Publication statusPublished - 15 Nov 2013

Fingerprint

Lesch-Nyhan Syndrome
Hypoxanthine Phosphoribosyltransferase
Guanine
MicroRNAs
Genes
Guanine Nucleotide Exchange Factors
Proteins
Monomeric GTP-Binding Proteins
Neurons
Cell Line
Gene Ontology
Multigene Family
Mesencephalon
Cytoskeleton
Knockout Mice
Cell Movement
purine
Fibroblasts
Phenotype
Gene Expression

Keywords

  • Animals
  • Cell Line
  • Cell Movement
  • Cerebral Cortex
  • Corpus Striatum
  • Cytoskeleton
  • Gene Ontology
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Hypoxanthine Phosphoribosyltransferase
  • Lesch-Nyhan Syndrome
  • Male
  • Mesencephalon
  • Mice
  • Mice, Knockout
  • MicroRNAs
  • Multigene Family
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction
  • rap1 GTP-Binding Proteins

Cite this

Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions : a role for EPAC in Lesch-Nyhan syndrome. / Guibinga, Ghiabe-Henri; Murray, Fiona; Barron, Nikki; Pandori, William; Hrustanovic, Gorjan.

In: Human Molecular Genetics, Vol. 22, No. 22, 15.11.2013, p. 4502-15.

Research output: Contribution to journalArticle

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abstract = "Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS.",
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T1 - Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions

T2 - a role for EPAC in Lesch-Nyhan syndrome

AU - Guibinga, Ghiabe-Henri

AU - Murray, Fiona

AU - Barron, Nikki

AU - Pandori, William

AU - Hrustanovic, Gorjan

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AB - Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS.

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KW - Cell Line

KW - Cell Movement

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KW - Hypoxanthine Phosphoribosyltransferase

KW - Lesch-Nyhan Syndrome

KW - Male

KW - Mesencephalon

KW - Mice

KW - Mice, Knockout

KW - MicroRNAs

KW - Multigene Family

KW - Oligonucleotide Array Sequence Analysis

KW - Signal Transduction

KW - rap1 GTP-Binding Proteins

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EP - 4515

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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ER -