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Adv Exp Med Biol. 2009;665:195-206.

Human clinical phenotype associated with FOXN1 mutations.

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Department of Pediatrics, Unit of Immunology, Federico II University, via S. Pansini, 5, 80131, Naples, Italy.


In humans, a proper immune response relies on the innate immunity, characterized by a rapid and nonspecific initial response to infections and later on the adaptive immunity, characterized by a specific response to a particular antigen. Disruption of any part of the orchestrated immune response results in the inability to control infections and, subsequently, in illness. An impairment of both effector arms of the specific immunity characterizes the clinical phenotype, known as severe combined immunodeficiency (SCID), which represents a heterogeneous group of inherited disorders due to abnormalities of T, B and NK cells. The first congenital SCID was described as spontaneous immunodeficiency in 1966 in mice and referred as Nude/SCID, based on the association of athymia with complete hairless. In 1996, the human equivalent of the murine Nude/SCID phenotype (MIM #601705) was reported. As in mice, also in humans this form is characterized by an intrinsic defect of the thymus, congenital alopecia and nail dystrophy and is due to mutations of the FOXN1 gene, as well. FOXN1 is mainly expressed in the thymus and skin epithelial cells, where it plays a critical role in differentiation and survival. FOXN1 belongs to the forkhead box (FOX) gene family that comprises a diverse group of 'winged helix' transcription factors involved in development, metabolism, cancer and aging. These transcription factors share the common property of being developmentally regulated and of directing tissue specific transcription and cell fate decisions. In immune system, alterations of FOXN1 result in a thymus anlage that lacks the capacity to generate mature and functional thymocytes. Because the significant expression levels of FOXN1 in skin elements, keratinocytes have been successfully used to support a full process of human T-cell development in vitro, resulting in the generation of mature T-cells from hematopoietic precursor cells (HPCs). This finding would imply a role for skin as a primary lymphoid organ. Thus, the present chapter will focus on the information that came out from the original description of the human Nude/SCID phenotype and on the role of FOXN1 and of the other members of FOX subfamilies in those immunological disorders characterized by abnormal T-cell development or abnormal T-cell regulatory homeostasis.

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