FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans

Du, Qiumei; Huynh, Larry; Coskun, Fatma S.; Molina, Erika; King, Matthew; Raj, Prithvi; Khan, Shaheen; Dozmorov, Igor; Seroogy, Christine M.; Wysocki, Christian; Padron, Grace T.; Yates, Tyler R.; Markert, M. Louise; Morena, M. Teresa de la; Oers, Nicolai S. C. van

doi:10.1172/jci127565

Cited by 37 publications

(49 citation statements)

References 56 publications

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“…Of the three mutant allele types, we are currently focusing on the Δ10 mutation, as we have observed a prominent “nude” phenotype in one homozygous Δ10/Δ10 NuRabbit ( Figure S4 ), and are continuing breeding to confirm. It is of interest to note that NuRabbits of different mutation types manifest variable extents of hair loss in the present work, which corroborates the findings in a recent report ( Du et al., 2019 ) where mice carrying different Foxn1 mutations showed different hair-loss phenotypes, although they all had thymic aplasia and were immunodeficient. Future studies are needed to elucidate the molecular mechanisms of how different FOXN1 mutations affect hair and thymus development in rabbits.…”

Section: Discussionsupporting

confidence: 92%

Development of the Nude Rabbit Model

et al. 2021

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Summary Loss-of-function mutations in the forkhead box N1 ( FOXN1 ) gene lead to nude severe combined immunodeficiency, a rare inherited syndrome characterized by athymia, severe T cell immunodeficiency, congenital alopecia, and nail dystrophy. We recently produced FOXN1 mutant nude rabbits (NuRabbits) by using CRISPR-Cas9. Here we report the establishment and maintenance of the NuRabbit colony. NuRabbits, like nude mice, are hairless, lack thymic development, and are immunodeficient. To demonstrate the functional applications of NuRabbits in biomedical research, we show that they can successfully serve as the recipient animals in xenotransplantation experiments using human induced pluripotent stem cells or tissue-engineered blood vessels. Our work presents the NuRabbit as a new member of the immunodeficient animal model family. The relatively large size and long lifespan of NuRabbits offer unique applications in regenerative medicine, cancer research, and the study of a variety of other human conditions, including immunodeficiency.

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Section: Discussionsupporting

confidence: 92%

Development of the Nude Rabbit Model

et al. 2021

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“…The North American experience so far highlights that even when a thymic stromal defect is genetically and functionally confirmed early, evaluating the best therapeutic approach remains difficult in the case of rare, novel defects. This is the case, for example, in regards to the management of infants with selective T-cell lymphopenia and low TREC levels at birth who have been diagnosed with hypomorphic heterozygous FOXN1 mutations since the introduction of NBS ( 132 , 133 ). None displayed alopecia totalis and nail dystrophy was seen in approximately half the reported cases only.…”

Section: Abnormalities Of Thymic Stromal Development and Functionmentioning

confidence: 99%

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

2021

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Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

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“…Whilst nude SCID is exceedingly rare, with only a handful of cases reported, the inclusion of TREC analysis in NBS programmes has identified a number of patients with hypomorphic compound heterozygous and heterozygous mutations in FOXN1 [ 123 , 124 ]. These include heterozygous carriers of nude SCID-associated mutations, as well as a variety of novel, mainly frameshift mutations affecting the forkhead and C-terminal domains [ 123 , 124 ]. Intriguingly, none have had congenital alopecia, but nail dystrophy is present in approximately half [ 123 , 124 ].…”

Section: Foxn1 Deficiencymentioning

confidence: 99%

“…These include heterozygous carriers of nude SCID-associated mutations, as well as a variety of novel, mainly frameshift mutations affecting the forkhead and C-terminal domains [ 123 , 124 ]. Intriguingly, none have had congenital alopecia, but nail dystrophy is present in approximately half [ 123 , 124 ]. The spectrum of immune deficiency is variable.…”

Section: Foxn1 Deficiencymentioning

confidence: 99%

Inborn errors of thymic stromal cell development and function

2020

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As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue.

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FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans

Abstract: Conflict of interest: MLM developed thymus transplantation intellectual property, which has been licensed to Enzyvant Therapeutics. Both MLM and Duke University may benefit financially if the technology is commercially successful in the future.

Cited by 37 publications

References 56 publications

Development of the Nude Rabbit Model

Development of the Nude Rabbit Model

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Inborn errors of thymic stromal cell development and function

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