Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study compared the interaction between ethanol and gamma-aminobutyric acid (GABA)-mediated current responses elicited in several immortalized cell lines and stably transfected cells, as well as in cultured and acutely dissociated rat cerebellar Purkinje cells. Only cell lines that were found previously to possess functional GABAA receptors were examined in this study. Under identical recording conditions, ethanol (10-200 mM) exerted no effect on GABA-induced currents in any of the cell lines or stably transfected cells tested in this study. However, GABA responses monitored in both primary culture and acutely dissociated Purkinje cells were significantly potentiated by ethanol (25 and 50 mM). Mouse pancreatic cells (RINm5F) were insensitive to both diazepam and ethanol suggesting the expression of a GABAA receptor isoform lacking a gamma subunit. Immortalized neuroblastoma IMR-32 cells displayed GABA responses that could be distinguished based on differential sensitivity to diazepam. However, none of the IMR-32 cells displayed GABA responses that were sensitive to modulation by ethanol. GABA responses in the stably transfected cell lines, PA3 (alpha1beta1gamma2L) and WSS-1 (alpha1beta2gamma2), were also unaffected by exposure to ethanol. In Purkinje cells acutely dissociated from the neonatal cerebellum, the ethanol-induced potentiation of GABA-induced current response could be observed before postnatal day 7, when only the gamma2S but not the gamma2L splice variant is expressed. This indicates that the gamma2L subunit is not necessary for an ethanol-induced potentiation of GABAA receptor-mediated response to become manifest. In addition, the results point to inherent differences that should be taken into account in interpreting comparative data between native and recombinant GABAA receptors.
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PMID:Ethanol-GABAA receptor interactions: a comparison between cell lines and cerebellar Purkinje cells. 945 26

The syndromes of Sotos and Weaver are paradigmatic of the daily nosologic difficulties faced by clinical geneticists attempting to diagnose and counsel, and to give accurate prognoses in cases of extensive phenotypic overlap between molecularly undefined entities. Vertebrate development is constrained into only very few final or common developmental paths; therefore, no developmental anomaly seen in humans is unique to ("pathognomonic" of) one syndrome. Thus, it is not surprising that prenatal overgrowth occurs in several syndromes, including the Sotos and Weaver syndromes. Are they sufficiently different in other respects to allow the postulation of locus (rather than allele) heterogeneity? Phenotypic data in both conditions are biased because of ascertainment of propositi, and the apparent differences between them may be entirely artificial as they were between the G and BBB syndromes. On the other hand, the Sotos syndrome may be a cancer syndrome, the Weaver syndrome not (though a neuroblastoma was reported in the latter); in the former there is also remarkably advanced dental maturation rarely commented on in the latter. In Weaver syndrome there are more conspicuous contractures and a facial appearance that experts find convincingly different from that of Sotos individuals. Nevertheless, the hypothesis of locus heterogeneity is testable; at the moment we are inclined to favor the hypothesis of allele heterogeneity. An international effort is required to map, isolate, and sequence the causal gene or genes.
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PMID:The syndromes of Sotos and Weaver: reports and review. 978 11

Cell lines are commonly used for studying recombinant heterooligomeric ion channels with defined subunit composition. Such studies often ignore the contribution of endogenous proteins in the assembly of mature channels. We examined whether an endogenous subunit was required for the functional expression of gamma-aminobutyric acid type A (GABA(A)) receptors in WSS-1 cells, HEK293 cells stably expressing recombinant alpha1 and gamma2 subunits. Our pharmacological and RT-PCR analyses of GABA(A) receptors and their mRNAs in WSS-1 cells confirm the presence of alpha1 and gamma2 subunits and suggest the existence of an endogenous beta3 subunit. Whole-cell GABA-evoked currents recorded from untransfected WSS-1 cells were blocked by bicuculline methiodide and enhanced by anesthetics and anticonvulsants including the subunit-selective compounds diazepam and loreclezole. These data suggest that, in addition to the gamma2 subunit, WSS-1 cell receptors also contain beta2/3 subunits. RT-PCR revealed that WSS-1 cells and parental HEK293 cells contain beta3 mRNA. We examined the contribution of the beta3 subunit in the function of receptors formed by expression of alpha1 and gamma2S subunits. Untransfected HEK293 cells were unresponsive to GABA. Cells transfected with alpha1 and gamma2S cDNAs displayed small diazepam and loreclezole responsive GABA-activated currents. By contrast, the expression of alpha1 and gamma2S cDNAs in the neuroblastoma NB41A3 cell line, that lacks beta subunit mRNAs, failed to produce functional receptors. These data reaffirm that alpha1 and gamma2S subunits alone do not form functional GABA(A) receptors and that receptors of WSS-1 cells contain alpha1, beta3 and gamma2S subunits.
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PMID:The influence of an endogenous beta3 subunit on recombinant GABA(A) receptor assembly and pharmacology in WSS-1 cells and transiently transfected HEK293 cells. 1072 82

Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma have been reported in children with Weaver syndrome. We present a third description of a patient with Weaver syndrome and neuroblastoma. In a child with phenotypic characteristics consistent with Weaver syndrome, evaluation for neuroblastoma should be considered.
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PMID:Weaver syndrome and neuroblastoma. 1901 74

Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes EZH2 and NSD1, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for DNMT3A, the co-occurrence of a duplication involving this gene and a pathogenic alteration in EZH2 in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.
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PMID:Co-occurrence of a maternally inherited DNMT3A duplication and a paternally inherited pathogenic variant in EZH2 in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a DNMT3A dosage effect? 2980 53