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 reads24,989,074 Total variants called23,146 Substitutions Total (novel)21,224 (1796) Synonymous9,936 Nonsense71 Missense8,121 Splice site 37 Non coding RNAs 58 Indels1,922 chromosome 11 region Total (novel)67 (8) Synonymous (novel) 26 (1) Nonsense (novel)0 (0) Missense (novel)15 (1) Splice site (novel) 0 (0) Indels0 Chromosome 18 region Total (novel)14 (0) Synonymous (novel) 6 (0) Nonsense (novel)0 (0) Missense (novel)8 (0) Splice site (novel) 0 (0) Indels0 FADD C105W Fas-Associated Death Domain protein (FADD) Tourneur et al. TREIMM, 2010 Decreased protein expression level Impaired Fas-FADD interaction FADD DD Fas DD C105W 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-TCR+ T cells - Increased serum levels of FasL and IL 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: Jean-Laurent Casanova Minji Byun Avinash Abhyankar Paris: Anne Puel United Kingdom: David McDonald Neil V Morgan Chris M Bacon Eamonn Maher Sophie Hambleton San Diego: Lakshmanane Premkumar Stefan J Riedl Singapore: Jean-Pierre Abastado Alessandra Nardin Charlene Tow