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Introduction to WP2: The Genetic Etiology of PADs

Positional cloning of disease causing genes has proven to be very successful in the identification of many defects in primary immunodeficiency diseases [1].
This consortium has collected more than 150 families with PAD including informative consanguineous families, and has recently published four candidate loci linkage papers identifying genetic susceptibility loci on chromosomes 4q, 5p, 6p, and 16q [2-5], However, the disease causing genes still remain elusive. Moreover, the consortium has recently collected 300 patients with sporadic CVID and 300 patients with selective IgAD, in whom we aim to search for the etiology of these diseases by molecular/genetic analysis in order to define the underlying molecular/genetic defect(s).

[1] Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. Notarangelo L, Casanova JL, Conley ME, Chapel H, Fischer A, Puck J, Roifman C, Seger R, Geha RS; International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. Journal: J Allergy Clin Immunol., 2006, 117: 883-96.
[2] Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Finck A, Van der Meer JW, Schaffer AA, Pfannstiel J, Fieschi C, Plebani A, Webster AD, Hammarstrom L, Grimbacher B. Eur J Hum Genet. 2006;14:867-75.
[3] Schaffer AA, Pfannstiel J, Webster AD, Plebani A, Hammarstrom L, Grimbacher B. Analysis of families with common variable immunodeficiency (CVID) and IgA deficiency suggests linkage of CVID to chromosome 16q. Hum Genet. 2005 Nov, 22:1-5.
[4] 15. Braig D.U., A.A. Schäffer, E. Glocker, U. Salzer, K. Warnatz, H.H. Peter, Grimbacher B. Linkage of Autosomal Dominant Common Variable Immunodeficiency to Chromosome 5p and Evidence for Locus Heterogeneity. Hum Genet. 2003, 112:369-378.
[5] Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. Kralovicova J, Hammarstrom L, Plebani A, Webster AD, Vorechovsky I. J Immunol. 2003;170:2765-75.

Project 1: Positional Cloning and Linkage studies

Common Variable Immunodeficiency (CVID) is a primary antibody immunodeficiency characterized by low immunoblobulin levels and low or normal B cell numbers. The genetic cause of this disease is unknown for the majority of cases. CVID may occur in an autosomal dominant (AD-CVID) trait or sporadically, but autosomal recessive (AR-CVID) families are also reported.

Project 2: Genetic association studies

The future direction of this project will be to recruit additional patients to run GWS on a sufficiently large replication cohort, aiming to identify both MHC and non-MHC susceptibility loci in patients with IgAD. Furthermore, we will try to identify multicase CVID families for mapping of susceptibility genes.

Project 3: The Candidate Gene Approach

Functional candidate genes for antibody deficiencies will be sought and evaluated on genetics and functional grounds.