Transcript Splice‐site (novel)

Human FADD deficiency
Alexandre Bolze
PhD director: Pr. Jean-Laurent Casanova
St. Giles Laboratory of Human Genetics of Infectious Diseases
Rockefeller University, New York 10065, NY
January 18, 2011
Clinical Presentation
- Fatal Invasive pneumoccocal disease
- Functional Hyposplenism
- Severe viral infections
- Cardiac malformations
Hypothesis
We Hypothesized that this new syndrome would segregate
as an autosomal-recessive trait.
Linkage analysis and whole-exome sequencing
Genetic analysis
Total number of reads
Total variants called
Total (novel)
Synonymous
Nonsense
Substitutions
Missense
Splice‐site
Non‐coding RNAs
Indels
Total (novel)
Synonymous
(novel)
chromosome 11
Nonsense (novel)
region
Missense (novel)
Splice‐site (novel)
Indels
Total (novel)
Synonymous
(novel)
Chromosome 18
Nonsense (novel)
region
Missense (novel)
Splice‐site (novel)
Indels
24,989,074
23,146
21,224 (1796)
9,936
71
8,121
37
58
1,922
67 (8)
26 (1)
0 (0)
15 (1)
0 (0)
0
14 (0)
6 (0)
0 (0)
8 (0)
0 (0)
0
FADD C105W
Fas-Associated Death Domain protein
(FADD)
Tourneur et al. TREIMM, 2010
Decreased protein expression level
Impaired Fas-FADD interaction
C105W
Fas DD
FADD DD
Impaired antiviral immunity (1)
VSV infection in EBV-B cells. MOI=1
Impaired antiviral immunity (2)
VSV infection in
EBV-B cells.
Impaired spleen architecture?
ALPS ?
Biological features of ALPS
- Increased number of CD4-CD8-TCRαβ+ T cells
- Increased serum levels of FasL and IL-10.
- Impaired lymphocyte apoptosis in vivo and in vitro on EBV-B cells
Conclusions and Questions
-Whole-exome sequencing and whole-genome sequencing are great
ways to find new immunodeficiencies and will probably redefine the
immunology pathways in the near future.
- C105W FADD homozygous mutation in humans leads to:
- impaired anti-viral immunity
- fatal invasive pneumococcal disease
- functional hyposplenism
- biological features of ALPS but no clinical phenotypes
Questions remaining:
- mechanism and role of FADD in the spleen architecture
- How to explain that the patients do not have splenomegaly or
lymphadenopathy?
- Role of FADD in the development of the heart
New York:
United Kingdom:
Jean-Laurent Casanova
Minji Byun
Avinash Abhyankar
David McDonald
Neil V Morgan
Chris M Bacon
Eamonn Maher
Sophie Hambleton
Paris:
Anne Puel
San Diego:
Singapore:
Jean-Pierre Abastado
Alessandra Nardin
Charlene Tow
Lakshmanane Premkumar
Stefan J Riedl