Human Molecular Genetics (HUM MOL GENET)

Publications in this journal

• Article: Cytoglobin has bimodal - tumour suppressor and oncogene functions in lung cancer cell lines

  Urszula Oleksiewicz, Triantafillos Liloglou, Kalliopi-Maria Tasopoulou, Nikoleta Daskoulidou, Julie Bryan, John R. Gosney, John K. Field, George Xinarianos
  Human Molecular Genetics 04/2013;
• Article: Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery.

  Mirsa N, Vasieva O.O, Marson T, Pirmohamed M
  Human Molecular Genetics 11/2011; 20(22):438-94.
• Article: Alpha-synuclein levels modulate Huntington’s disease in mice.

  Brown, Rubinsztein
  Human Molecular Genetics 01/2011;
• Article: Coordinated diurnal regulation of genes from the Dlk1-Dio3 imprinted domain: implications for regulation of clusters of non-paralogous genes.

  Stéphane Labialle, Lanjian Yang, Xuan Ruan, Aude Villemain, Jennifer V Schmidt, Arturo Hernandez, Tim Wiltshire, Nicolas Cermakian, Anna K Naumova
  [show abstract] [hide abstract]
  ABSTRACT: The functioning of the genome is tightly related to its architecture. Therefore, understanding the relationship between different regulatory mechanisms and the organization of chromosomal domains is essential for understanding genome regulation. The majority of imprinted genes are assembled into clusters, share common regulatory elements, and, hence, represent an attractive model for studies of regulation of clusters of non-paralogous genes. Here, we investigated the relationship between genomic imprinting and diurnal regulation of genes from the imprinted domain of mouse chromosome 12. We compared gene expression patterns in C57BL/6 mice and congenic mice that carry the imprinted region from a Mus musculus molossinus strain MOLF/Ei. In the C57BL/6 mice, a putative enhancer/oscillator regulated the expression of only Mico1/Mico1os, whereas in the congenic mice its influence was spread onto Rtl1as, Dio3 and Dio3os, i.e. the distal part of the imprinted domain, resulting in coordinated diurnal variation in expression of five genes. Using additional congenic strains we determined that in C57BL/6 the effect of the putative enhancer/oscillator was attenuated by a linked dominant trans-acting factor located in the distal portion of chromosome 12. Our data demonstrate that (i) in adult organs, mRNA levels of several imprinted genes vary during the day, (ii) genetic variation may remove constraints on the influence of an enhancer and lead to spreading of its effect onto neighboring genes, thereby generating genotype-dependent expression patterns and (iii) different regulatory mechanisms within the same domain act independently and do not seem to interfere with each other.
  Human Molecular Genetics 02/2008; 17(1):15-26.
• Article: Extensive contribution of embryonic stem cells to the development of an evolutionarily divergent host.

  Andy Peng Xiang, Frank Fuxiang Mao, Wei-Qiang Li, Donghyun Park, Bao-Feng Ma, Tao Wang, Tammy W Vallender, Eric J Vallender, Li Zhang, Jaehyun Lee, John A Waters, Xiu-Ming Zhang, Xin-Bing Yu, Shu-Nong Li, Bruce T Lahn
  [show abstract] [hide abstract]
  ABSTRACT: The full potential of embryonic stem (ES) cells to generate precise cell lineages and complex tissues can be best realized when they are differentiated in vivo-i.e. in developing blastocysts. Owing to various practical and ethical constraints, however, it is impossible to introduce ES cells of certain species into blastocysts of the same species. One solution is to introduce ES cells into blastocysts of a different species. However, it is not known whether ES cells can contribute extensively to chimerism when placed into blastocysts of a distantly related species. Here, we address this question using two divergent species, Apodemus sylvaticus and Mus musculus, whose genome sequence differs by approximately 18% from each other. Despite this considerable evolutionary distance, injection of Apodemus ES cells into Mus blastocysts led to viable chimeras bearing extensive Apodemus contributions to all major organs, including the germline, with Apodemus contribution reaching approximately 40% in some tissues. Immunostaining showed that Apodemus ES cells have differentiated into a wide range of cell types in the chimeras. Our results thus provide a proof of principle for the feasibility of differentiating ES cells into a wide range of cell types and perhaps even complex tissues by allowing them to develop in vivo in an evolutionarily divergent host-a strategy that may have important applications in research and therapy. Furthermore, our study demonstrates that mammalian evolution can proceed at two starkly contrasting levels: significant divergence in genome and proteome sequence, yet striking conservation in developmental programs.
  Human Molecular Genetics 02/2008; 17(1):27-37.
• Article: In vivo response to high-resolution variation of Tbx1 mRNA dosage.

  Zhen Zhang, Antonio Baldini
  [show abstract] [hide abstract]
  ABSTRACT: Mouse modeling of haploinsufficiency syndromes and, in general, of syndromes caused by gene dosage imbalance, is often unsatisfactory because loss (or gain) of one copy of the gene of interest is insufficient to recapitulate the disease phenotype. In this study, we use Tbx1 mutants, which model one of the most common haploinsufficiency disorders, the 22q11.2DS/DiGeorge/Velocardiofacial syndrome, to test the feasibility of high resolution dosage manipulation to generate mouse models that more closely resemble the human syndrome. We used nine different genotypes at the Tbx1 locus that are associated with progressively lower mRNA levels in vivo. We show that penetrance and expressivity of different phenotypic features became more severe as the dosage diminished, as expected, but the response was strikingly non-linear, with extreme examples such as neonatal lethality, which changed from 2 to 100% after a dosage reduction of just approximately 16%. Furthermore, heart phenotype variability, extreme in the human syndrome but very limited, or absent, in the standard knockout model, was seen when mRNA level was approximately 20% of normal level, suggesting that there is a threshold level associated with unstable balance, which can be perturbed by chance events. Overall, our data suggest that there are developmental process-specific gene dosage thresholds beyond which the phenotype worsens very rapidly with very small mRNA level reductions.
  Human Molecular Genetics 02/2008; 17(1):150-7.
• Article: The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.

  Scott V Dindot, Barbara A Antalffy, Meenakshi B Bhattacharjee, Arthur L Beaudet
  [show abstract] [hide abstract]
  ABSTRACT: Loss of function of the maternally inherited allele for the UBE3A ubiquitin ligase gene causes Angelman syndrome (AS), which is characterized by severe neurological impairment and motor dysfunction. In addition, UBE3A lies within chromosome 15q11-q13 region, where maternal, but not paternal, duplications cause autism. The UBE3A gene product, E6-AP, has been shown to function both as an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. However, the specific role of E6-AP in the brain, or how loss of function of E6-AP results in AS, is unclear. Herein, we show, using a recombinant transgenic mouse expressing a Ube3a(YFP) fusion gene, that the maternal Ube3a(YFP) allele is upregulated and preferentially expressed in neurons, and that the fusion protein, E6-AP:YFP, is enriched in the nucleus and dendrites in vivo. We also show that E6-AP:YFP localizes to the nucleus and to presynaptic and postsynaptic compartments in cultured hippocampal neurons. Furthermore, we show that cerebellar Purkinje cell number and dendritic branching are not affected in Ube3a maternal-deficient mice, but that dendritic spine development, including spine morphology, number and length, is affected on cerebellar Purkinje cells and on pyramidal neurons in the hippocampus and cortex. Collectively, these data suggest that the neurological deficits observed in AS patients and in AS mice may result from specific abnormalities in synaptic development and/or plasticity.
  Human Molecular Genetics 02/2008; 17(1):111-8.
• Article: Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder.

  Sven Cichon, Ingeborg Winge, Manuel Mattheisen, Alexander Georgi, Anna Karpushova, Jan Freudenberg, Yun Freudenberg-Hua, Gulia Babadjanova, Ann Van Den Bogaert, Lilia I Abramova, [......], Per M Knappskog, Jeffrey McKinney, Wolfgang Maier, Rami Abou Jamra, Thomas G Schulze, Johannes Schumacher, Peter Propping, Marcella Rietschel, Jan Haavik, Markus M Nöthen
  [show abstract] [hide abstract]
  ABSTRACT: The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5' region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 5'-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.
  Human Molecular Genetics 02/2008; 17(1):87-97.
• Article: Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.

  T Flatscher-Bader, N Zuvela, N Landis, P A Wilce
  [show abstract] [hide abstract]
  ABSTRACT: Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.
  Human Molecular Genetics 02/2008; 17(1):38-51.
• Article: Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice.

  Megan A Albertelli, Orla A O'Mahony, Michele Brogley, Jeffrey Tosoian, Mara Steinkamp, Stephanie Daignault, Kirk Wojno, Diane M Robins
  [show abstract] [hide abstract]
  ABSTRACT: The androgen receptor (AR) is involved in the initiation and progression of prostate cancer and its transition to androgen independence. Genetic variation in AR may contribute to disease risk and has been studied for a polymorphic N-terminal glutamine (Q) tract that shows population heterogeneity. While the length of this tract is known to affect AR in vitro, association with disease is complicated by genetic and environmental factors that have led to discordant epidemiological findings. To clarify the effect of Q tract polymorphism on prostate cancer, we created mice bearing humanized AR genes (h/mAr) varying in Q tract length. ARs with short Q tracts (12Q), which are transcriptionally more active, induce earlier disease in the transgene-induced TRAMP prostate cancer model than alleles with median (21Q) or long (48Q) tracts. Disease length varies within each genotype, with greater differentiation and AR expression in slower growing tumors. Remarkably, following androgen ablation, Q tract length has effects that are also allele-dependent and in directions opposite to those in hormone intact mice. Differences in AR activity conferred by Q tract length thus appear to direct distinct pathways of androgen-independent as well as androgen-dependent progression, and highlight substantial risk that may be associated with alterations in the androgen axis. This AR allelic series in humanized mice provides an experimental paradigm to dissect the role of AR in prostate cancer initiation and progression, to model response to treatment and to test therapies targeted specifically to the human AR.
  Human Molecular Genetics 02/2008; 17(1):98-110.
• Article: Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on day 9.5 of development.

  Rocío M Rivera, Paula Stein, Jamie R Weaver, Jesse Mager, Richard M Schultz, Marisa S Bartolomei
  [show abstract] [hide abstract]
  ABSTRACT: In vitro culture of mouse embryos results in loss of imprinting. The aim of the present study was to examine how two of the techniques commonly used during assisted reproduction, namely embryo culture and embryo transfer, affect genomic imprinting after implantation in the mouse. F1 hybrid mouse embryos were subjected to three experimental conditions: control (unmanipulated), embryo transfer and in-vitro-culture followed by embryo transfer. Concepti were collected on d9.5 of development and allelic expression determination of ten imprinted genes (H19, Snrpn, Igf2, Kcnq1ot1, Cdkn1c, Kcnq1, Mknr3, Ascl2, Zim1, Peg3) was performed. Although control concepti had monoallelic imprinted gene expression in all tissues, both manipulated groups had aberrant expression of one or more imprinted genes in the yolk sac and placenta. Culture further exacerbated the effects of transfer by increasing the number of genes with aberrant allelic expression in extraembryonic, as well as embryonic tissues. Additionally, placentae of both groups of manipulated concepti exhibited reduced levels of Igf2 mRNA and increased levels of Ascl2 mRNA when compared with their unmanipulated counterparts. Furthermore, we show that biallelic expression of Kcnq1ot1 coincided with loss of methylation on the maternal allele of the KvDMR1 locus, a phenotype often associated with the human syndrome Beckwith-Wiedemann. In conclusion, our results show that even the most basic manipulation used during human-assisted reproduction, namely, embryo transfer, can lead to misexpression of several imprinted genes during post-implantation development. Additionally, our results serve as a cautionary tale for gene expression studies in which embryo transfer is used.
  Human Molecular Genetics 02/2008; 17(1):1-14.