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Dive into the research topics where Beth Wilmot is active.

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Featured researches published by Beth Wilmot.


Nature Genetics | 2006

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

Neil V. Morgan; Shawn K. Westaway; Jenny Morton; Allison Gregory; Paul Gissen; Scott Sonek; Hakan Cangul; Jason Coryell; Natalie Canham; Nardo Nardocci; Giovanna Zorzi; Shanaz Pasha; Diana Rodriguez; Isabelle Desguerre; Amar Mubaidin; Enrico Bertini; Richard C. Trembath; Alessandro Simonati; Carolyn Schanen; Colin A. Johnson; Barbara Levinson; C. Geoffrey Woods; Beth Wilmot; Patricia L. Kramer; Jane Gitschier; Eamonn R. Maher; Susan J. Hayflick

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.


The New England Journal of Medicine | 2013

Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML

Julia E. Maxson; Jason Gotlib; Daniel A. Pollyea; Angela G. Fleischman; Anupriya Agarwal; Christopher A. Eide; Daniel Bottomly; Beth Wilmot; Shannon McWeeney; Cristina E. Tognon; J. Blake Pond; Robert H. Collins; Basem Goueli; Stephen T. Oh; Michael W. Deininger; Bill H. Chang; Marc Loriaux; Brian J. Druker; Jeffrey W. Tyner

BACKGROUND The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms. METHODS To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).


Movement Disorders | 2004

Distribution, type, and origin of Parkin mutations: Review and case studies

Katja Hedrich; Cordula Eskelson; Beth Wilmot; Karen Marder; Juliette Harris; J. Garrels; Helen Meija‐Santana; Peter Vieregge; Helfried Jacobs; Susan Bressman; Anthony E. Lang; Martin Kann; Giovanni Abbruzzese; Paolo Martinelli; Eberhard Schwinger; Laurie J. Ozelius; Peter P. Pramstaller; Christine Klein; Patricia L. Kramer

Early‐onset Parkinsons disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty‐eight mutation‐positive individuals, available family members, and 62 mutation‐negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.


Blood | 2010

A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

Shannon McWeeney; Lucy C. Pemberton; Marc Loriaux; Kristina Vartanian; Stephanie G. Willis; Gregory S. Yochum; Beth Wilmot; Yaron Turpaz; Raji Pillai; Brian J. Druker; Jennifer L. Snead; Mary MacPartlin; Stephen G. O'Brien; Junia V. Melo; Thoralf Lange; Christina A. Harrington; Michael W. Deininger

In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph(+) metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34(+) cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph(+) metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated beta-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity.


Proceedings of the National Academy of Sciences of the United States of America | 2009

A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia

Wei Tian; Yi Fu; Anna Garcia-Elias; José M. Fernández-Fernández; Rubén Vicente; Patricia L. Kramer; Robert F. Klein; Robert Hitzemann; Eric S. Orwoll; Beth Wilmot; Shannon McWeeney; Miguel A. Valverde; David M. Cohen

Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration ≤135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4P19S allele relative to the wild-type allele. Subjects with the minor allele were 2.4−6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the TRPV4P19S polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.


PLOS ONE | 2013

Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progression through c-Myc Upregulation

Lina Gao; Jacob Schwartzman; Angela Gibbs; Robert Lisac; Richard Kleinschmidt; Beth Wilmot; Daniel Bottomly; Ilsa Coleman; Peter S. Nelson; Shannon McWeeney; Joshi J. Alumkal

The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer – AR and c-Myc – and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.


Trends in Genetics | 2014

Functional and genomic context in pathway analysis of GWAS data

Michael Mooney; Joel T. Nigg; Shannon McWeeney; Beth Wilmot

Gene set analysis (GSA) is a promising tool for uncovering the polygenic effects associated with complex diseases. However, the available techniques reflect a wide variety of hypotheses about how genetic effects interact to contribute to disease susceptibility. The lack of consensus about the best way to perform GSA has led to confusion in the field and has made it difficult to compare results across methods. A clear understanding of the various choices made during GSA - such as how gene sets are defined, how single-nucleotide polymorphisms (SNPs) are assigned to genes, and how individual SNP-level effects are aggregated to produce gene- or pathway-level effects - will improve the interpretability and comparability of results across methods and studies. In this review we provide an overview of the various data sources used to construct gene sets and the statistical methods used to test for gene set association, as well as provide guidelines for ensuring the comparability of results.


Genes, Brain and Behavior | 2013

Genes, Behavior, and Next-Generation RNA Sequencing

Robert Hitzemann; Daniel Bottomly; Priscila Darakjian; Nicole A.R. Walter; Ovidu Iancu; Robert P. Searles; Beth Wilmot; Shannon McWeeney

Advances in next-generation sequencing suggest that RNA-Seq is poised to supplant microarray-based approaches for transcriptome analysis. This article briefly reviews the use of microarrays in the brain-behavior context and then illustrates why RNA-Seq is a superior strategy. Compared with microarrays, RNA-Seq has a greater dynamic range, detects both coding and noncoding RNAs, is superior for gene network construction, detects alternative spliced transcripts, detects allele specific expression and can be used to extract genotype information, e.g. nonsynonymous coding single nucleotide polymorphisms. Examples of where RNA-Seq has been used to assess brain gene expression are provided. Despite the advantages of RNA-Seq, some disadvantages remain. These include the high cost of RNA-Seq and the computational complexities associated with data analysis. RNA-Seq embraces the complexity of the transcriptome and provides a mechanism to understand the underlying regulatory code; the potential to inform the brain-behavior relationship is substantial.


Journal of Child Psychology and Psychiatry | 2016

Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2

Beth Wilmot; Rebecca C. Fry; Lisa Smeester; Erica D. Musser; Jonathan Mill; Joel T. Nigg

BACKGROUND Peripheral epigenetic marks hold promise for understanding psychiatric illness and may represent fingerprints of gene-environment interactions. We conducted an initial examination of CpG methylation variation in children with or without attention-deficit/hyperactivity disorder (ADHD). METHODS Children age 7-12 were recruited, screened, evaluated and assigned to ADHD or non-ADHD groups by defined research criteria. Two independent age-matched samples were examined, a discovery set (n = 92, all boys, half control, half ADHD) and a confirmation set (n = 20, half ADHD, all boys). 5-methylcytosine levels were quantified in salivary DNA using the Illumina 450 K HumanMethylation array. Genes for which multiple probes were nominally significant and had a beta difference of at least 2% were evaluated for biological relevance and prioritized for confirmation and sequence validation. Gene pathways were explored and described. RESULTS Two genes met the criteria for confirmation testing, VIPR2 and MYT1L; both had multiple probes meeting cutoffs and strong biological relevance. Probes on VIPR2 passed FDR correction in the confirmation set and were confirmed through bisulfite sequencing. Enrichment analysis suggested involvement of gene sets or pathways related to inflammatory processes and modulation of monoamine and cholinergic neurotransmission. CONCLUSIONS Although it is unknown to what extent CpG methylation seen in peripheral tissue reflect transcriptomic changes in the brain, these initial results indicate that peripheral DNA methylation markers in ADHD may be promising and suggest targeted hypotheses for future study in larger samples.


Neurobiology of Aging | 2008

Translational gene mapping of cognitive decline

Beth Wilmot; Shannon McWeeney; Randal R. Nixon; Thomas J. Montine; Jamie Laut; Christina A. Harrington; Jeffrey Kaye; Patricia L. Kramer

The ability to maintain cognitive function during aging is a complex process subject to genetic and environmental influences. Alzheimers disease (AD) is the most common disorder causing cognitive decline among the elderly. Among those with AD, there is broad variation in the relationship between AD neuropathology and clinical manifestations of dementia. Differences in expression of genes involved in neural processing pathways may contribute to individual differences in maintenance of cognitive function. We performed whole genome expression profiling of RNA obtained from frontal cortex of clinically non-demented and AD subjects to identify genes associated with brain aging and cognitive decline. Genetic mapping information and biological function annotation were incorporated to highlight genes of particular interest. The candidate genes identified in this study were compared with those from two other studies in different tissues to identify common underlying transcriptional profiles. In addition to confirming sweeping transcriptomal differences documented in previous studies of cognitive decline, we present new evidence for up-regulation of actin-related processes and down-regulation of translation, RNA processing and localization, and vesicle-mediated transport in individuals with cognitive decline.

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