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)

Neuroblastomas (NBs) show complex patterns of genetic abnormalities, which may include amplification of the MYCN gene, deletion of 1p, or a gain of DNA at 17q, the last being the most frequent observation in NB tumors. However, the specific genes and the molecular mechanisms responsible for development and progression of NB remain poorly understood. We investigated aberrations of DNA copy number in 25 NB cell lines using comparative genomic hybridization and identified a minimal common region of gain at 17q23. Although gain of distal 17q is the most powerful genetic predictor of adverse outcome currently available for patients with NB, thus far, no potential target genes have been reported for that region. Therefore, we defined the 17q23 amplicon in detail and determined expression levels of 15 genes located within the smallest region of overlap observed among our NB cell lines to identify the most likely target gene(s). Among them, seven (CLTC, VMP1, delta-tubulin, RPS6KB1, FLJ22087, APPBP2, and PPM1D) were consistently overexpressed through increases in regional copy number. Analysis of expression levels of those seven genes in 32 primary NB tumors revealed a significant correlation between higher expression and poorer clinical outcome only with respect to PPM1D. Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death. Taken together, our results indicate that PPM1D is the most likely target of the 17q23 gain/amplification in NB tumors and may have an important role in the pathogenesis of this disease.
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PMID:PPM1D is a potential target for 17q gain in neuroblastoma. 1270 77

Diagnostic exome sequencing has recently emerged as an invaluable tool in determining the molecular etiology of cases involving dysmorphism and developmental delay that are otherwise unexplained by more traditional methods of genetic testing. Our patient was large for gestational age at 35 weeks, delivered to a 27-year-old primigravid Caucasian whose pregnancy was complicated by preeclampsia. Neonatal period was notable for hypoglycemia, apnea, bradycardia, hyperbilirubinemia, grade I intraventricular hemorrhage, subdural hematoma, laryngomalacia, hypotonia, and feeding difficulties. The patient had numerous minor dysmorphic features. At three and a half years of age, she has global developmental delays and nystagmus, and is being followed for a mediastinal neuroblastoma that is currently in remission. Karyotype and oligo-microarray were normal. Whole-exome, next generation sequencing (NGS) coupled to bioinformatic filtering and expert medical review at Ambry Genetics revealed 14 mutations in 9 genes, and these genes underwent medical review. A heterozygous de novo frameshift mutation, c.2737_2738dupGA p.D913Efs*59, in which two nucleotides are duplicated in exon 17 of the CLTC gene, results in substitution of glutamic acid for aspartic acid at position 913 of the protein, as well as a frame shift that results in a premature termination codon situated 58 amino acids downstream. Clathrin Heavy Chain 1 (CHC1) has been shown to play an important role in the brain for vesicle recycling and neurotransmitter release at pre-synaptic nerve terminals. There is also evidence implicating it in the proper development of the placenta during the early stages of pregnancy. The CLTC alteration identified herein is likely to provide an explanation for the patient's adverse phenotype. Ongoing functional studies will further define the impact of this alteration on CHC1 function and consequently, human disease.
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PMID:CLTC as a clinically novel gene associated with multiple malformations and developmental delay. 2682 84