Download Albena Jordanova - the Department of Molecular Genetics

Albena Jordanova
Neurogenetics Group
VIB Department of Molecular Genetics
University of Antwerp
MSc in Biochemistry and Microbiology, Sofia University
St. Kliment Ohridski, 1992
PhD in Molecular Genetics, Sofia Medical University, 1999
Specialty in Medical Biology, Sofia Medical University, 2001
Associate Professor in Molecular Neurosciences, University of
Antwerp, since 2007
Associate Professor in Human Molecular Genetics: Sofia Medical
University, since 2009
E-mail:
Phone:
[email protected]
+32 (0) 3 265 1025
Current Project Members
PhD students: Ricardo Gonçalves, Magdalena Zimon, Biljana Ermanoska
Technicians: Els De Vriendt, Tinne Ooms
Keywords
molecular genetics – neurodegeneration – aminoacyl-tRNA synthetases – inbred populations
Science
My research focuses on the identification and characterization of disease-causing genes and
pathways implicated in the molecular etiology of neurological disorders, like inherited
peripheral neuropathies (CMT) and inherited epilepsies. For this purpose we use two major
research strategies:
- unraveling the role of aminoacyl-tRNA synthetases in peripheral neurodegeneration as a
tool for understanding the molecular pathomechanisms of peripheral neuropathies;
- identification of novel disease-causing genes and mutations implicated in inherited forms of
peripheral neuropathies and epilepsies using population and family based genetic
approaches.
Aminoacyl-tRNA synthetases are ubiquitously expressed and essential proteins, involved in
the initial steps of protein biosynthesis and therefore indispensible for cell survival. We
recently reported that specific mutations in the tyrosyl-tRNA synthetase (TyrRS, YARS) cause
Dominant Intermediate Charcot-Marie-Tooth disease type C (DI-CMTC) - a genetic and
phenotypic variant of inherited peripheral neuropathy. It is enigmatic how mutations in this
protein can lead to a peculiar specificity of the pathophysiological deficit, characterized by
axonal degeneration of the peripheral nerves only. We were the first to establish that the DICMTC phenotype is not due to haploinsufficiency of enzymatic activity, but to a gain-offunction alteration of the mutant YARS or interference with an unknown function of the wild
type protein. To unravel the alternative function of YARS in the nervous system we
developed the first Drosophila model for inherited peripheral neuropathy, as well as
appropriate cellular and yeast systems. We apply a genetic approach of an unbiased, gain-offunction modifier screen to identify genes, whose function modulates neuron-specific mutant
YARS phenotypes in fly. The most promising putative modifiers are studied in details using
different experimental paradigms. In this way we aim to pinpoint the main molecular
pathways where this protein is involved and to simultaneously unravel known or novel
molecular pathomechanisms implicated in CMT.
In a parallel research direction we tackle the complex molecular pathology of clinically and
genetically heterogeneous disorders, like inherited peripheral neuropathies and inherited
epilepsies, using the advantages of founder or inbred populations. Our starting material are
unique collections of nuclear inbred families with autosomal-recessive CMT forms coming
from different geographic regions and ethnic groups of the world, as well as epileptic families
belonging to the isolated population of European Gypsies. Using genetic approaches for
mapping of recessive disorders combined with the most recent advances in genotyping
technologies, we aim to create a powerful tool for disease-causing locus and gene
identification. The identification of genes implicated in different forms of peripheral
neuropathies and epilepsies contributes to the understanding of the pathophysiology of these
disorders by revealing new disease mechanisms or strengthening the importance of the
known ones. The mutations that are found allow genotype-phenotype correlations and have
an important impact on the diagnostics, genetic counseling and disease prevention. Our
findings provide the rational basis for the development of novel drugs and therapeutic
concepts.
Selected Publications
Suls A, Velizarova R, Yordanova I, Deprez L, Van Dyck T, Wauters J, Guergueltcheva V, Claes
L, Kremensky I, Jordanova A.*, De Jonghe P.*: Four generations of epilepsy caused by an
inherited microdeletion of the SCN1A gene. Neurology 75: 72-76 (2010), *-equally
contributing authors
Storkebaum E, Leitão-Gonçalves R, Godenschwege T, Nangle L, Mejia M, Bosmans I, Ooms
T, Jacobs A, Van Dijck P, Yang XL, Schimmel P, Norga K, Timmerman V, Callaerts P*,
Jordanova A*. Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in
Drosophila features of human Charcot-Marie-Tooth neuropathy. Proc Natl Acad Sci U S A.
106(28):11782-7 (2009), *-equally contributing authors
Jordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K, Dewil M, Jacobs A, De Vriendt
E, Dierick I, Van Gerwen V, Guergueltcheva V, Rao CV, Tournev I, Gondim FA, D’Hooghe M,
Callaerts P, Van Den Bosch L, Timmermans J-P, Robberecht W, Gettemans J, Thevelein JM,
De Jonghe P, Kremensky I, Timmerman V. Disrupted function and axonal distribution of
mutant tyrosyl-tRNA-synthetase associated with dominant intermediate Charcot-Marie-Tooth
neuropathy. Nature Genetics 38(2): 197-202 (2006)
Jordanova A, Thomas FP, Guergueltcheva V, Tournev I, Gondim FA, Ishpekova B, De
Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I,
Timmerman V.: Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome
1p34-p35. American Journal of Human Genetics 73(6):1423-30 (2003)
Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler I, Mancias P, Papasozomenos Ch, Terespolsky D, Potocki L, Brown C, Shy M, Rita D,
Tournev I, Kremensky I, Lupski JR, Timmerman V. Mutations in the neurofilament light chain
gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126: 590-597
(2003)
Kalaydjieva A, Perez-Lezuan A, Angelicheva D, Onengut A, Dye D, Bosshard N, Jordanova
A, Savov A, Yanakiev P, Radeva B, Hallmayer J, Markov A, Nedkova V, Tournev I, Aneva L,
Gitzelmann R.: A founder mutation in the GK1 gene is responsible for galactokinase
deficiency in Roma (Gypsies). American Journal of Human Genetics 65: 1299-1307 (1999)