Cicle de Conferències en Malalties Rares, VHIR, Barcelona, 16 Des 2014 Rare diseases as platform to develop novel therapeutic strategies: the example of Fanconi anemia Dr. Jordi Surrallés Catedràtic de Genética Professor ICREA-Acadèmia Universitat Autònoma de Barcelona Genome Instability Group: http://gig.uab.cat
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"Rare diseases as platform to develop novel therapeutic strategies: the example of Fanconi anemia" by Prof. Jordi Surrallés Calonge
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Cicle de Conferències en Malalties Rares, VHIR, Barcelona, 16 Des 2014
Rare diseases as platform to develop
novel therapeutic strategies: the
example of Fanconi anemia
Dr. Jordi Surrallés
Catedràtic de Genética
Professor ICREA-Acadèmia
Universitat Autònoma de Barcelona
Genome Instability Group: http://gig.uab.cat
Fanconi anemia
http://www.malaltiaamagada.com
A tale: Arnau has a hidden disease
Garaycoechea and Patel (2014) Blood 123:26-34
Bone marrow failure in Fanconi anemia
Disease evolution in Fanconi Anemia
Kutler et al., Blood, 2003
Chromosome fragility in Fanconi anemia
C. Group Gene Reference
FA-A FANCA Lo Ten Foe et al. Nature Genetics 1996
FABC Consortium. Nature Genetics 1996
FA-B FANCB Meetei et al Nature Genetics 2004
FA-C FANCC Strathdee et al. Nature, 1992
FA-D1 FANCD1/BRCA2 Howlett et al. Science, 2002
FA-D2 FANCD2 Timmers et al. Mol Cell, 2001
FA-E FANCE De Winter et al. Am. J. Hum Genet 2000
FA-F FANCF De Winter et al. Nature Genet. 2000
FA-G FANCG De Winter et al. Nature Genet. 1998
FA-I FANCI Smogorzewska et al. Cell 2007
FA-J FANCJ/BRIP1 Levran et al. Nature Genet. 2005; Levitus et al. Nature Genet. 2005;
FA-L FANCL Ruhikanta et al. Nature Genet. 2003
FA-M FANCM Meetei et al Nature Genetics 2005
FA-N FANCN/PALB2 Reid et al Nature Genetics 2007
Xia et al Nature Genetics 2007
FA-O FANCO/RAD51C Vaz et al Nature Genetics 2010
FA-P FANCP/SLX4 Stoepker et al Nature Genetics 2011
Kim et al Nature Genetics 2011
15+1 complementation Groups in Fanconi Anemia
Interstrand crosslink repair (ICLR)
Fork stalling
Unhooking
Translesion sythesis
Recombination
1 10 100 1000
100
80
60
40
20
0
FANC-C
FANC-G
FANC-F
FANC-A
MMC (nM)
Re
lati
ve
su
rviv
al
%
Empty
Retroviral subtyping of FA
Genetic subtyping of 143 Spanish FA patients
Callen et al., Blood 2005; Casado et al., J Med Genet 2007; Kalb et al Am J Hum Genet
2007; Castella et al Blood 2011
Unassigned
whole exome sequencing
501500
498 499
FA 287
Mutations in the XPF nuclease lead to three
rare disorders: XP, XFE-progeria and FA
Xeroderma pigmentosum XFE-progeria Fanconi anemia
FANCQ alias for XPF in HUGO
Bogliolo et al., 2013, Am J Hum Genet
Interstrand crosslink
repair (ICLR)
Fork stalling
Unhooking
Homologous recombination
Nucleotide excision
repair (NER)
recognition
dual incision
excision
DNA synthesis
ligation
UV
NER
ICLR
Xeroderma pigmentosum
NER
ICLR
Xeroderma pigmentosum
NER
ICLR
Fanconi anemia
NER
ICLR
Fanconi anemia
NER ICLR
Progeria
NER ICLR
Progeria
1 gene (XPF), 2 repair pathways, 3 syndromes
Bogliolo et al., Am J Hum Genet (2013)
UV skin sensitivity anemia Anemia + UV skin
sensitivity
C. Group Gene Reference
FA-A FANCA Lo Ten Foe et al. Nature Genetics 1996
FABC Consortium. Nature Genetics 1996
FA-B FANCB Meetei et al Nature Genetics 2004
FA-C FANCC Strathdee et al. Nature, 1992
FA-D1 FANCD1/BRCA2 Howlett et al. Science, 2002
FA-D2 FANCD2 Timmers et al. Mol Cell, 2001
FA-E FANCE De Winter et al. Am. J. Hum Genet 2000
FA-F FANCF De Winter et al. Nature Genet. 2000
FA-G FANCG De Winter et al. Nature Genet. 1998
FA-I FANCI Smogorzewska et al. Cell 2007
FA-J FANCJ/BRIP1 Levran et al. Nature Genet. 2005;Levitus et al. Nature Genet. 2005;
FA-L FANCL Ruhikanta et al. Nature Genet. 2003
FA-M FANCM Meetei et al Nature Genetics 2005
FA-N FANCN/PALB2 Reid et al Nature Genetics 2007
Xia et al Nature Genetics 2007
FA-O FANCO/RAD51C Vaz et al Nature Genetics 2010
FA-P FANCP/SLX4 Stoepker et al Nature Genetics 2011
Kim et al Nature Genetics 2011
FA-Q FANCQ/ERCC4 Bogliolo et al Am J Hum Genet 2013
16 complementation Groups in Fanconi Anemia
DNA damage response
Ataxia Telang.
Nijmegen
Fanconi
Bloom
Seckle
Breast cancer risk in BRCA1/2 mutation carriers
April 2005
Synthetic lethality in cancer therapeutics
Synthetic lethality in cancer treatment
Lord and Ashworth BMC Biology 2010 8:38 doi:10.1186/1741-7007-8-38