Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients.

Research at C.C.'s lab was partially supported by FEDER (Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III) (PI13/00160 and PI14/00025), Fundación Inocente Inocente, and the ARIMMORA EU/FP7 project and by donations from the Asociación Española del Síndrome de Wolf Hirschhorn (AESWH), the Fundación Síndrome de Wolf-Hirschhorn or 4p- (FSWH4p), FECYT Precipita, and Fundación Ramón Areces. E.C.-S. was partially supported by a JAE-PreDoc fellowship from the Spanish National Research Council (CSIC, FEDER) and was a Residencia de Estudiantes Fellow. N.D.-S. was partially supported by a JAE-intro studentship from the Spanish National Research Council (CSIC) (JAEINT_15_01981). Research at K.U.'s lab was partially supported by the JSTP PRESTO program (4201) and Grants-in-Aid for Scientific Research (22131003 and 15H01345) from MEXT of Japan. P.P.R. is a National Cancer Center and American Society of Hematology Fellow. J.A.S. is a Leukemia & Lymphoma Society (LLS) scholar and NCC and ASH fellow and is supported by NIH grants R01GM086852 and R01GM112192. Research at M.L.M.F.'s lab was partially supported by Instituto de Salud Carlos III and Fundación 1.000 sobre Defectos Congénitos. CIBERER is an initiative of ISCIII, Ministry of Economy and Competitiveness of Spain. V.D. was partially supported by Ministry of Science and Innovation through the Programa tecnicos de apoyo (PTA) from 2012 to 2014. A.E.-C. is funded by the RED-BIO project of the Spanish National Bioinformatics Institute (INB) under grant number PT13/0001/0044. The INB is funded by the Spanish National Health Institute Carlos III (ISCIII) and the Spanish Ministry of Economy and Competitiveness (MINECO). M.D. was funded by the Ministry of Economy and Competitiveness of Spain (PTA2014-09515-I). H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). P.P.R. was financed by NIH grant K99GM117302.