To further the understanding of the molecular basis of human diseases and to prepare trainees to undertake research in this and related areas.
The group brings together individuals with divergent but complementary areas of expertise and skills which they apply to understand the molecular basis of diabetes, muscular dystrophies, and other disorders. One of the unique aspects of this group is their access to special patient populations. The isolated aboriginal and Hutterite populations affected with limb girdle muscular dystrophies, for example, allow for powerful genetic analyses. The common prevalence of Type II Diabetes with very early onset in isolated populations allows the study of factors, both genetic and environmental, that contribute to this major health problem of today. In addition, the members have a diverse set of technical expertise that has allowed them to maintain a presence in highly competitive fields.
MEMBERS:
Klaus Wrogemann, M.D., Ph.D.
Head of Research Group
Professor, Departments of Biochemistry & Medical Genetics and Pediatrics & Child Health
Tel.: [204] 789-3701, Fax.: [204] 789-3900 email.: K_Wrogemann@umanitoba.ca
Lab Site: http://home.cc.umanitoba.ca/~wrogemn/
Expertise: Muscular Dystrophies, Positional Cloning, Linkage analysis, Energy Metabolism. See also COS
R. Daniel Gietz, Ph.D.
Associate Head of Research Group
Associate Professor, Departments of Biochemistry & Medical Genetics and Pediatrics & Child Health
Tel.: [204] 789-3458, Fax.: [204] 789-3900 email.: gietz@cc.umanitoba.ca
Lab Site:http://home.cc.umanitoba.ca/~gietz//
Expertise: Yeast Molecular Biology, DNA Repair and Application of the two-hybrid system to human disease
Hao Ding, Ph.D.
Assistant Professor, CRC ChairII, Department of Biochemistry and Medical Genetics
Tel.: [204] 480-1300, Fax.: [204] 789-3900 email.: H_Ding@umanitoba.ca
Expertise: Transgenic animals, mouse pathology, development, cancer.
Cheryl R. Greenberg, M.D., C.M., FRCPC,
Professor and Head, Department of Pediatrics & Child Health,Professor, Department of Biochemistry & Medical Genetics
Tel.: [204] 787-2711, Fax.: [204] 787-1419 email.: cgreenberg@hsc.mb.ca
Expertise: Clinical Genetics, Metabolic Diseases, Applied Molecular Genetics
Steven N. Pind, Ph.D., Assistant Professor, Department of Biochemistry & Medical Genetics
Tel.: [204] 789-3603, Fax.: [204] 789-3900 email: spind@cc.umanitoba.ca
Expertise: Cystic Fibrosis, Protein expression and biosynthesis, Protein-protein interactions,
3-phosphoglycerate dehydrogenase deficiency
Mojgan Rastegar, PhD, Assistant Professor, Regenerative Medicine Program, Faculty of MedicineDepartment of Biochemistry & Medical Genetics; Department of Immunology; Scientist, Manitoba Institute of Child Health (MICH)
Tel.: Office [204] 272-3108, Lab [204] 272-3145, Fax: [204] 789-3900 e-mail: rastegar@cc.umanitoba.ca
Lab Site: http://rastegar.biochem.umanitoba.ca/index.html
Expertise: Epigenetics, Embryonic Stem Cells (ESC), Neural Stem Cells (NSC), Stem Cell Differentiation, Neurogenesis, HOX Proteins, Rett Syndrome, Gene Therapy, Viral Vectors
Barbara Triggs-Raine, Ph.D.,
Professor, Department of Biochemistry & Medical Genetics
Tel.: [204] 789-3218, Fax.: [204] 789-3900 email.: traine@ms.umanitoba.ca
Expertise: Lysosomal Storage Diseases, Diabetes Mellitus, Molecular Biology
Teresa Zelinski, Ph.D.
Professor, Departments of Pediatrics & Child Health and Biochemistry & Medical Genetics
Tel.: [204] 789-3244, Fax: [204] 789-3900 e-mail: zelinski@ms.umanitoba.ca
Expertise: Genetic linkage analysis, blood groups
ASSOCIATE MEMBERS:
Gilbert Arthur, Ph.D.
Professor, Department of Biochemistry & Medical Genetics
Tel.: [204] 789-3758, Fax.: [204] 789-3900 email.: arthur@ms.umanitoba.ca
Expertise: Signal Transduction, Lipid Metabolism
Geoff Hicks, Ph.D.
Associate Professor, Department of Biochemistry & Medical Genetics & Manitoba Inst. of Cell Biology
Director,Mammalian Functional Genomics Centre (MFG)
Tel: [204] 787-2133; Fax: [204] 787-2190 e-mail: hicksgg@cc.umanitoba.ca
Lab Site: http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/index.htm
Expertise:Functional analysis of the mammalian genome using Tagged-Sequence Mutagenesis to disrupt genes expressed in mouse embryo-derived stem (ES) cells
Jörg Stetefeld, Ph.D.
Associate Professor, CRC Chair II, Department of Chemistry
Tel: [204] 474-9731Fax:[204] 474-7608 e-mail: stetefel@cc.umanitoba.ca
Lab Site: http://www.umanitoba.ca/chemistry/people/stetefeld/
Expertise: Integrated approach X-ray crystallography and solution NMR. Extracellular signaling, Storage and delivery function of coiled-coil domains, Enzyme catalysis.
SELECTED PUBLICATIONS:
(chosen to demonstrate the diverse expertise of group members as well as recent progress)
Sedigheh Abedini, Wei Chen, Masoumeh Hosseini, Farkhondeh Behjati, Stefan Haas, Payman Jamali, Agnes Zecha, Marzieh Mohseni, Lucia Püttmann, Leyla Nouri Vahid, Corinna Jensen, Lia Abbasi Moheb, Melanie Bienek, Farzaneh Larti, Ines Mueller, Robert Weissmann, Hossein Darvish, Klaus Wrogemann, Valeh Hadavi, Bettina Lipkowitz, Sahar Esmaeeli-Nieh, Dagmar Wieczorek, Saghar Ghasemi Firouzabadi, Monika Cohen, Zohreh Fattahi, Imma Rost, Faezeh Mojahedi, Christoph Hertzberg, Atefeh Dehghan, Anna Rajab, Mohammad Javad Soltani Banavandi, Julia Hoffer,Masoumeh Falah, Luciana Musante, Vera Kalscheuer, Reinhard Ullmann, AndreasWalther Kuss, Andreas Tzschach, Kimia Kahrizi, H. Hilger Ropers. Next generation sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63 (2011).
Hao Hu; Katinka Eggers; Wei Chen; Masoud Garshasbi; M. Mahdi Motazacker; Klaus Wrogemann, Kimia Kahrizi; Andreas Tzschach, Masoumeh Hosseini, Ideh Bahman, Tim Hucho, Martina Mühlenhoff, Rita Gerardy-Schahn, Hossein Najmabadi, H. Hilger Ropers, Andreas Walter Kuss. ST3GAL3 mutations impair intellectual functioning. Am J. Hum. Genet. 89(3): 407-414 (2011).
Armistead J, Khatkar S, Meyer B, Mark BL, Patel N, Coghlan G, Lamont RE, Liu S, Wiechert J, Cattini PA, Koetter P, Wrogemann K, Greenberg CR, Entian KD, Zelinski T, Triggs-Raine B. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome. Am J Hum Genet. 84(6):728-39 (2009)
Jadin L, Wu X, Ding H, Frost GI, Onclinx C, Triggs-Raine B, Flamion B. Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?
FASEB J. 4316-26 (2008)
Arthur G, Bittman R. The inhibition of cell signaling pathways by antitumor ether lipids.
Biochim Biophys Acta 1390:85-102 (1998).
Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage.
Proc Natl Acad Sci U S A. 101(44):15718-23 (2004).
Ding H, Wu X, Bostrom H, Kim I, Wong N, Tsoi B, O'Rourke M, Koh GY, Soriano P, Betsholtz C, Hart TC, Marazita ML, Field LL, Tam PP, Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling.
Nat Genet. 36(10):1111-6 (2004).
Ding H, Schertzer M, Wu X, Gertsenstein M, Selig S, Kammori M, Pourvali R, Poon S, Vulto I, Chavez E, Tam PP, Nagy A, Lansdorp PM. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein.
Cell. 117(7):873-86 (2004)
Coghlan G, Zelinski T. DNA microsatellite and linkage analysis supports the inclusion of LOCR in the Rh blood group system.
Transfusion. 43(4):440-4. (2003)
Ryan E. Lamont, J.C. Loredo-Osti, Nicole M. Roslin, Jill Mauthe, Gail Coghlan, Edward Nylen, Danielle Frappier, A. Micheil Innes, Edward G. Lemire, R. Brian Lowry, Cheryl R. Greenberg, Barbara L. Triggs-Raine, Kenneth Morgan, Klaus Wrogemann, T. Mary Fujiwara, and Teresa Zelinski. A Locus for Bowen-Conradi Syndrome Maps to Chromosome Region 12p13.3.
Am. J. Med. Genet.,132A: 136-43 (2005).
Zhou X, Lu X, Richard C, Ziong W, Litchfield DW, Bittman R, and Arthur G. 1-O-Octadecyl-2-O-methlglycerophosphocholine inhibits the transduction of growth signals via the MAP kinase cascade in MCF-7 cells by interfering in the membrane association of Raf-1.
J Clin Invest 98:937-944 (1996).
Gietz RD, Triggs-Raine B, Robbins A, Graham KC, Woods RA. . Identification of proteins that interact with a protein of interest: applications of the yeast two-hybrid system.
Mol Cell Biochem 172:67-79 (1997).
Paetkau DW, Riese JA, MacMorran WS, Woods RA, and Gietz RD (1994) Interaction between the yeast Rad7 and Sir3 proteins: implications for DNA repair and chromatin structure.
Genes and Dev. 8: 2035-2045.
Serfas KD, Bose D, Patel L, Wrogemann K, Phillips MS, MacLennan DH, Greenberg CR Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family.
Anesthesiology 84:322-9 (1996).
Weiler T, Greenberg CR, Nylen E, Halliday W, Morgan K, Eggertson D, and Wrogemann K. Limb girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.
Am. J. Hum. Genet. 59:872-878 (1996).
Cao Z, Petroulakis E, Salo T, Triggs-Raine B Benign HEXA mutations, C739T(R247W) and C745T(R249W), cause beta-hexosaminidase A pseudodeficiency by reducing the alpha-subunit protein levels.
J. Biol. Chem. 272:14975-14982 (1997).
Greenberg CR, Reimer D, Singal R, Triggs-Raine B, Chudley AE, Dilling LA, Philipps S, Haworth JC, Seargeant LE, and Goodman SI. A G-to-T transversion at the +5 position of intron 1 in the glutaryl CoA dehydrogenase gene is associated with the Island Lake variant of glutaric acidemica type I.
Hum. Mol. Genet. 4: 493-495 (1995).
Hicks GG, Shi EG, Li, X-M, Li, C-H, Pawlak, M, and Ruley HE. Functional genomics in mice tagged sequence mutagenesis.
Nature Genetics, 16: 338-344 (1997).
Shuttleworth TL, Wilson MD, Wicklow BA, Wilkins JA, Triggs-Raine BL. Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3.
J Biol Chem. 277(25):23008-18 (2002).
Triggs-Raine BL, Kirkpatrick RD, Kelly SL, Norquay LD, Cattini PA, Yamagata K, Hanley AJ, Zinman B, Harris SB, Barrett PH, Hegele RA. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community.
Proc Natl Acad Sci U S A: 99(7):4614-9 (2002).
Triggs-Raine B, Mahuran DJ, Gravel RA. Naturally occurring mutations in GM2 gangliosidosis: a compendium.
Adv Genet:44:199-224 (2001).
Mark BL, Wasney GA, Salo TJ, Khan AR, Cao Z, Robbins PW, James MN, Triggs-Raine BL. Structural and functional characterization of Streptomyces plicatus beta-N-acetylhexosaminidase by comparative molecular modeling and site-directed mutagenesis
J Biol Chem 273:19618-24 (1998).
Jerome CA, Scherer SW, Tsui L-C, Gietz RD, and Triggs-Raine BL . Assignment of growth factor receptor bound protein 10 (GRB10) to human chromosome 7p11.2-p12.
Genomics 40: 215-216 (1997).
Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing.
Cell 83:129-35 (1995).
Patrick Frosk, Tracey Weiler, Edward Nylen, Thangirala Sudha, Cheryl R. Greenberg, Kenneth Morgan, T. Mary Fujiwara, Klaus Wrogemann. Limb girdle muscular dystrophy type 2H (LGMD2H) associated with mutation in TRIM32, a putative E3 ubiquitin ligase gene.
Am. J. Hum. Genet. 70: 663-672 (2002).
Patrick Frosk, Cheryl R. Greenberg, Alysa A. P. Tennese, Ryan Lamont, Edward Nylen, Cheryl Hirst, Danielle Frappier, Nicole M. Roslin, Michaela Zaik, Kate Bushby, Volker Straub, Mayana Zatz, Kenneth Morgan, T. Mary Fujiwara, Klaus Wrogemann. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations.
Human Mutation, 25: 38-44 (2005).
Pind S, Riordan JR, Williams DB . Participation of the endoplasmic reticulum chaperonecalnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator.
J. Biol. Chem. 269: 12784-12788 (1994).
Weiler T, Greenberg CR, Zelinski T, Nylen E, Coghlan G, Crumley MJ, Fujiwara TM, Morgan K, Wrogemann K. A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.
Am J Hum Genet 63:140-7 (1998).
Stetefeld J, Jenny M and Burkhard P. Intersubunit signaling in glutamate-1-semialdehyde aminomutase Proc Natl Acad Sci U S A. 103 (37): 13688-93 (2006).
Haeussinger D, Ahrens T, Aberle T., Engel J, Stetefeld J and Grzesiek S. Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography EMBO J. 23: 1699-1708 (2004).
Rastegar M., Hotta A., Pasceri P., Makarem M., Cheung A., Elliot S., Adachi M., Jones, F.S., Park K.J., Clarke I., Dirks P. and Ellis J. MECP2 Isoform-Specific Vectors with Regulated Expression for Rett Syndrome Gene Therapy. PLoS ONE 4(8): e6810. doi:10.1371 (2009)
Delcuve G.P., Rastegar M. and Davie JR. Epigenetic Control. J. Cell. Physiol. 166 (1) (2009)
Ellis J., Hotta A., and Rastegar M. Retrovirus silencing by an epigenetic TRIM. Cell 131(1), 13-14 (2007)
Nolte C.*, Rastegar M.*, Amores A., Bouchard M., Grote D., Maas R., Nagy Kovacs E., Postlethwait J., Rambaldi I., Rowan Sh., Zhang F., and Featherstone M. Stereospecificity and PAX6 function direct Hoxd4 neural enhancer activity along the antero-posterior axis. Dev Biol. 15-299(2): 582-93 (2006) *equal authorship
FUTURE PLANS:
In recent years the major thrust in the study of genetic diseases has been in the discovery of genes causing single gene disorders. This is only the first step in the molecular pathology of such disorders. Working out the details will require renewed interest in protein chemistry, protein-protein interactions, signal transduction, cell biology approaches, and the use of simpler model organisms. In addition, even single gene disorders will often be influenced in their clinical presentation and severity by the interaction with other genes. In the simplest case one may deal with di-genic diseases and/or modifier genes, but many more common diseases are influenced by the constellation and interaction of numerous genes. Their identification is generally known as quantitative trait analysis and the field of functional genomics will come into play as well. We intend to develop and expand our expertise to meet these challenges and will reorganize our group into the Centre for the Investigation of Genetic Diseases, which will embrace a considerably wider group of complementing expertise. It is dedicated to the Study of Development, Growth and Metabolism of Children.
A major emphasis on our group activities will be the training of future investigators. We are meeting this challenge through regular formal lab meetings in which the expertise of the various members of the group will benefit members of all laboratories, including the technical support staff.