Lesch‐Nyhan syndrome and its pathogenesis: Purine concentrations in plasma and urine with metabolite profiles in CSF

Harkness, R. A.; McCreanor, G. M.; Watts, R. W. E.

doi:10.1007/bf01800365

Cited by 47 publications

(24 citation statements)

References 48 publications

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“…The genetic defect of recycling hypoxanthine and guanine leads to the metabolic and neurological hallmarks of the disease; i.e., hyperuricemia, dystonia, and above all, the severely aberrant neurobehavioral effect of self-mutilation associated with severe basal ganglia dopamine (DA) depletion and defective DA uptake in both the human LND patients and in the HPRT knockout mouse. 1,2 The mechanisms responsible for the central nervous system (CNS) disorder are poorly understood. Molecular genetic studies of HPRT deficiency in the mouse knockout model and in human patients with LND have revealed few robust clues to the development of the neurological phenotype.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of the Housekeeping Gene Hypoxanthine–Guanine Phosphoribosyltransferase (HPRT) Dysregulates Neurogenesis

2010

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Neuronal transcription factors play vital roles in the specification and development of neurons, including dopaminergic (DA) neurons. Mutations in the gene encoding the purine biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause the resulting intractable and largely untreatable neurological impairment of Lesch-Nyhan disease (LND). The disorder is associated with a defect in basal ganglia DA pathways. The mechanisms connecting the purine metabolic defect and the central nervous system (CNS) phenotype are poorly understood but have been presumed to reflect a developmental defect of DA neurons. We have examined the effect of HPRT deficiency on the differentiation of neurons in the well-established human (NT2) embryonic carcinoma neurogenesis model. We have used a retrovirus expressing a small hairpin RNA (shRNA) to knock down HPRT gene expression and have examined the expression of a number of transcription factors essential for neuronal differentiation and marker genes involved in DA biosynthetic pathway. HPRT-deficient NT2 cells demonstrate aberrant expression of several transcription factors and DA markers. Although differentiated HPRT-deficient neurons also demonstrate a striking deficit in neurite outgrowth during differentiation, resulting neurons demonstrate wild-type electrophysiological properties. These results represent direct experimental evidence for aberrant neurogenesis in HPRT deficiency and suggest developmental roles for other housekeeping genes in neurodevelopmental disease.

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Section: Introductionmentioning

confidence: 99%

Deficiency of the Housekeeping Gene Hypoxanthine–Guanine Phosphoribosyltransferase (HPRT) Dysregulates Neurogenesis

2010

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“…The cause of this profoundly debilitating disease remains unknown. A common factor in LNS is that patients exhibit a characteristically raised level of hypoxanthine in plasma (Rosenbloom et al, 1967;Harkness et al, 1988;Puig and Mateos, 1993), urine (Sweetman, 1968;Harkness et al, 1988), and cerebrospinal fluid (Rosenbloom et al, 1967;Sweetman, 1968;Harkness et al, 1988).…”

mentioning

confidence: 98%

Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome

Margaret

Stacey

Connolly

2001

J of Neuroscience Research

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Extracellular purines have essential roles in neuronal development; hence, disruptions in their metabolism as reported in Lesch Nyhan syndrome (LNS) could result in developmental abnormalities. The deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) in LNS leads to increased hypoxanthine and uric acid production. We have reported that HGPRT-deficient B103-4C neuroblastoma, a neuronal model of LNS, proliferated less and differentiated more than their HGPRT-positive B103 counterparts. Here, we sought to determine whether differences in proliferation and differentiation would occur when these cells were cultured in the presence of hypoxanthine or in a hypoxanthine-/serum-free chemically defined media (NBMN2). In media with 1% serum, hypoxanthine (50 microM) significantly increased the proliferation of both cell lines with a greater effect on B103-4C cells. In 1% serum media, hypoxanthine increased differentiation of B103 but decreased B103-4C differentiation. In NBMN2, B103 proliferated far more than B103-4C, but both cell types differentiated to the same extent. These results are interpreted to suggest that elevated levels of central nervous system (CNS) hypoxanthine as reported in LNS may affect neuronal development, and to implicate hypoxanthine and abnormal neuronal development as causative factors in the etiology of LNS.

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“…This view has found support by evidence that hypoxanthine-related metabolites accumulate to a greater degree than guanine-related metabolites, implying HGprt has a more biologically important role in recycling hypoxanthine than guanine (Sweetman and Nyhan 1970; Harkness et al 1988). Conversely, some studies suggest Gprt to be more relevant.…”

Section: Discussionmentioning

confidence: 97%

Do clinical features of Lesch‐Nyhan disease correlate more closely with hypoxanthine or guanine recycling?

Schretlen

Callon

Ward

et al. 2015

J of Inher Metab Disea

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Lesch-Nyhan disease (LND) is a rare, X-linked recessive neurodevelopmental disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme in the purine salvage pathway. HGprt has two functions; it recycles hypoxanthine and guanine. Which of these two functions is more relevant for pathogenesis is unclear because some evidence points to hypoxanthine recycling, but other evidence points to guanine recycling. In this study, we selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with LND, 11 with an attenuated variant of the disease (LNV), and 19 age-, sex-, and race-matched healthy controls (HC). Activity levels of both enzymes differed across groups (p< 0.0001), but only Gprt distinguished patients with LND from those with LNV (p<0.05). Gprt also showed slightly stronger correlations than Hprt with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These findings suggest that loss of guanine recycling might be more closely linked to the LND/LNV phenotype than loss of hypoxanthine recycling.

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Lesch‐Nyhan syndrome and its pathogenesis: Purine concentrations in plasma and urine with metabolite profiles in CSF

Cited by 47 publications

References 48 publications

Deficiency of the Housekeeping Gene Hypoxanthine–Guanine Phosphoribosyltransferase (HPRT) Dysregulates Neurogenesis

Deficiency of the Housekeeping Gene Hypoxanthine–Guanine Phosphoribosyltransferase (HPRT) Dysregulates Neurogenesis

Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome

Do clinical features of Lesch‐Nyhan disease correlate more closely with hypoxanthine or guanine recycling?

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