Alymphoid cystic thymic dysgenesis - FOXN1 gene mutation: a rare case report of two siblings

Alymphoid cystic thymic dysgenesis is a severe combined immunodeficiency (SCID) syndrome caused b y a mutation in fork head box N1 gene (FOXN1) on chromosome 17. It is a transcriptional factor regulating the development, differentiation and function of thymic epithelial cells; maintaining T-lineage progenitors in bone marrow; promoting terminal differentiation of epithelial cells of hair follicles. Mutation in FOXN1 is known to cause a rare disorder characterized by rudimentary thymus gland (primary lymphoid organ for T-cell differentiation), T-cell immunodeficiency, congenital alopecia totalis and nail dystrophy. Here we report two affected siblings from a non-consanguineous family with similar features of alopecia totalis, nail dystrophy and failure to thrive. The first child was a 7-month-old female baby, with history of two hospitalization in the past for lower respiratory tract infection, had left axillary lymphadenopathy (BCG adenitis), alopecia totalis, nail dystrophy and hepatosplenomegaly. Bronchoalveolar lavage secretion was positive for Mycobacterium tuberculosis and Pneumocystis carinii pneumonia by gene Xpert and polymerase chain reaction respectively. Immunodeficiency panel workup revealed combined T cell and B cell immunodeficiency, genetic analysis by whole exome sequencing revealed recessive missense mutation in exon 6 of FOXN1 gene on chromosome 17. Due to lack of sufficient literature it was reported as variant of unknown significance and to establish its clinical significance the carrier status of both the parents was established. Second child presented to us at 3 months of age, also had similar phenotypic features and on evaluation had very low lymphocyte subset count however mutational analysis could not be done in this child due to parent’s denial. Hence, we conclude this child also was affected.

Pleiotropic Functions of FoxN1: Regulating Different Target Genes during Embryogenesis and Nymph Molting in the Brown Planthopper

FoxN1 gene belongs to the forkhead box gene family that comprises a diverse group of “winged helix” transcription factors that have been implicated in a variety of biochemical and cellular processes. In the brown planthopper (BPH), FoxN1 is highly expressed in the ovaries and newly laid eggs, where it acted as an indispensable gene through its molecular targets to regulate early embryonic development. Moreover, the results of the RNAi experiments indicated that Nilaparvata lugens FoxN1 (NlFoxN1) exhibited pleiotropism: they not only affected the embryogenesis, but also played an important role in molting. RNA-seq and RNAi were further used to reveal potential target genes of NlFoxN1 in different stages. In the eggs, ten downregulated genes were defined as potential target genes of NlFoxN1 because of the similar expression patterns and functions with NlFoxN1. Knockdown of NlFoxN1 or any of these genes prevented the development of the eggs, resulting in a zero hatchability. In the nymphs, NlFoxN1 regulated the expression of a keratin gene, type I cytoskeletal keratin 9 (NlKrt9), to participate in the formation of an intermediate filament framework. Depletion of NlFoxN1 or NlKrt9 in nymphs, BPHs failed to shed their old cuticle during nymph-to-nymph or nymph-to-adult molting and the mortality was almost 100%. Altogether, the pleiotropic roles of NlFoxN1 during embryogenesis and nymph molting were supported by the ability to coordinate the temporal and spatial gene expression of their target genes.

Athymic Nude Mice as an Experimental Model for Cancer Treatment

Athymic nude mice, a murine strain bearing spontaneous deletion in the Foxn1 gene that causes deteriorated or absent thymus (which results in inhibited immune system with reduction of number of T cells), represent a widely used model in cancer research having long lasting history as a tool for preclinical testing of drugs. The review describes three models of athymic mice that utilize cancer cell lines to induce tumors. In addition, various methods that can be applied in order to evaluate activity of anticancer agents in these models are shown and discussed. Although each model has certain disadvantages, they are still considered as inevitable instruments in many fields of cancer research, particularly in finding new drugs that would more effectively combat the cancer disease or enhance the use of current chemotherapy. Finally, the review summarizes strengths and weaknesses as well as future perspectives of the athymic nude mice model in cancer research.