Altered palmitoylation and neuropathological deficits in mice lacking HIP14.

Huntingtin interacting protein 14 (HIP14, ZDHHC17) is a huntingtin (HTT) interacting protein with palmitoyl transferase activity. In order to interrogate the function of Hip14, we generated mice with disruption in their Hip14 gene. Hip14-/- mice displayed behavioral, biochemical and neuropathological defects that are reminiscent of Huntington disease (HD).

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

Background: Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia.

Diagnostic testing for vaccinomics: is the regulatory approval framework adequate? A comparison of Canada, the United States, and Europe.

Vaccinomics aims to integrate variability information from multiple levels of the biological hierarchy from genome to proteome to metabolome, and ways in which these biological parts interact with each other and the environment. Vaccinomics holds significant promise as a new public health tool in designing safer and more effective vaccines for both developed and developing countries. Vaccinomics tests that are envisioned to be used in tandem with vaccine-based health interventions could permit an informed forecast of individual and subpopulation variations in immune responses to vaccines, reduce adverse effects, and contribute to a foundation for rational and directed use of vaccines.

Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14.

Huntington disease (HD) is caused by polyglutamine expansion in the huntingtin (HTT) protein. Huntingtin-interacting protein 14 (HIP14), one of 23 DHHC domain-containing palmitoyl acyl transferases (PATs), binds to HTT and robustly palmitoylates HTT at cysteine 214. Mutant HTT exhibits reduced palmitoylation and interaction with HIP14, contributing to the neuronal dysfunction associated with HD.

The communication of pharmacogenetic research results: participants weigh in on their informational needs in a pilot study.

In this brief investigation, the informational needs of research participants [n = 62; mothers who had breastfed, taken codeine, and participated in a pharmacogenetic study] were probed during a counselling session in which they received their CYP2D6 pharmacogenetic research results and overall study results. In addition to the standard information, developed by a multidisciplinary team and provided to the participants, 38% of individuals had further questions related to potential adverse effects in babies, future codeine or medication use, heredity, and consequences for policies and programmes. The diversity and complexity of the questions raised support the need to communicate the results in the context of personalized genetic counselling information sessions.

Pharmacogenomics of serious adverse drug reactions in pediatric oncology.

Adverse drug reactions (ADRs) rank as one of the top ten leading causes of death and illness in the developed world. In cancer therapy, more patients are surviving cancer than ever before, but 40% of cancer survivors suffer life-threatening or permanently disabling severe ADRs and are left with long-term sequelae. ADRs are often more frequent and more severe in children, and the consequences for children who experience a severe ADR can be catastrophic.

Cutaneous adverse drug reactions in children: an analysis of reports from the Canadian Pharmacogenomics Network for Drug Safety (CPNDS).

Cutaneous adverse drug reactions (CADRs) are the most prevalent adverse drug reactions (ADRs) in hospitalized children, with an estimated rate of 2-3%. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) is a pan-Canadian active surveillance network identifying genomic biomarkers of risk for serious ADRs. The purpose of this paper is to describe the characteristics of paediatric CADR cases reported to the CPNDS from February 2005 to December 2008.

Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease.

Models of Huntington disease (HD) recapitulate some neuropathological features of the disease. However, a global natural history of neuroanatomy in a mouse expressing full-length huntingtin has not been conducted. We investigated neuropathological changes in the YAC128 murine model of HD using magnetic resonance imaging (MRI).

Pharmacogenomics of cardiovascular drugs and adverse effects in pediatrics.

Individual response to medication is highly variable. For many drugs, a substantial proportion of patients show suboptimal response at standard doses, whereas others experience adverse drug reactions (ADRs). Pharmacogenomics aims to identify genetic factors underlying this variability in drug response, providing solutions to improve drug efficacy and safety.

Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.

Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis.

Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage, and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype.

A grand challenge: providing benefits of clinical genetics to those in need.

Genetic research, techniques, and knowledge have rapidly expanded in the last two decades with the completion of the Human Genome Project and other major advances in discovery research and diagnostic technologies. Although these developments have obvious potential, they also raise significant challenges related to programs for the actual delivery of useful genetic testing and services. This challenge is particularly acute in rural and remote areas, where lack of access to genetic services is pervasive resulting in significant inequities in access and availability of services.

HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia.

Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10-100 times greater than in East Asia.

The dynamics of macrophage infiltration into the arterial wall during atherosclerotic lesion development in low-density lipoprotein receptor knockout mice.

Atherosclerosis is a progressive disease in which macrophages play an essential role. Macrophage infiltration into the arterial wall induces the development of an early atherosclerotic lesion. However, the dynamics of macrophage infiltration into the arterial wall during lesion progression remain poorly understood.

Regulatory approval for new pharmacogenomic tests: a comparative overview.

Pharmacogenomics is the study of how genetic variants affect the way in which an individual or subgroup responds to drugs. This developing field aims to inform individual drug therapy and to minimize adverse drug reactions (ADRs). It also promises great benefits in the drug development process.

Factors associated with experiences of genetic discrimination among individuals at risk for Huntington disease.

The purpose of this study was to identify factors that are associated with experiencing genetic discrimination (GD) among individuals at risk for Huntington disease (HD). Multivariable logistic regression analysis was used to examine factors associated with experiencing GD in data from a cross-sectional, self-report survey of 293 individuals at risk for HD. The study sample comprised 167 genetically tested respondents, and 66 who were not tested (80% response rate).

Optical properties of DAST in the THz range.

We report the far-infrared properties of the organic crystal DAST, a popular terahertz emitter, from 0.6-12 THz through use of a THz spectrometer incorporating air-plasma THz generation and electro-optic (EO) sampling in a poled EO polymer. We identify absorption features at 1.

Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo.

Caspase cleavage of huntingtin (htt) and nuclear htt accumulation represent early neuropathological changes in brains of patients with Huntington's disease (HD). However, the relationship between caspase cleavage of htt and caspase activation patterns in the pathogenesis of HD remains poorly understood. The lack of a phenotype in YAC mice expressing caspase-6-resistant (C6R) mutant htt (mhtt) highlights proteolysis of htt at the 586 aa caspase-6 (casp6) site as a key mechanism in the pathology of HD.

BDNF overexpression in the forebrain rescues Huntington's disease phenotypes in YAC128 mice.

Huntington's disease (HD) is caused by an expansion of the polyglutamine tract at the N terminus of huntingtin. This mutation reduces levels of BDNF in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis.

Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A.

YAC transgenic mice expressing poly(Q)-expanded full-length huntingtin (mhtt) recapitulate many behavioral and neuropathological features of Huntington disease (HD). We have previously observed a reduction in phosphorylation of mhtt at S421 in the presence of the mutation for HD. In addition, phosphorylation of normal S421-htt is reduced after excitotoxic stimulation of NMDA receptors (NMDARs).

Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease.

Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice.

Pharmacogenomics and active surveillance for serious adverse drug reactions in children.

Juxtaposing clinical pharmacology with human genetics, pharmacogenomics utilizes a patient's genetic information to identify genetic variants that have the potential to provide clinically relevant predictions of toxicity and efficacy. The goal is to develop personalized and genetic-based predictions of an individual's drug response and likelihood of experiencing an adverse drug reaction. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) has implemented active adverse drug reaction surveillance to monitor and discover genetic markers related to serious adverse drug reactions in the pediatric population.

Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions.

Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41).

Cholesterol defect is marked across multiple rodent models of Huntington's disease and is manifest in astrocytes.

Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis.

Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease.

Excitotoxicity plays a key role in the selective vulnerability of striatal neurons in Huntington disease (HD). Decreased glutamate uptake by glial cells could account for the excess glutamate at the synapse in patients as well as animal models of HD. The major molecule responsible for clearing glutamate at the synapses is glial glutamate transporter GLT-1.