# The Functions of Novel FOXN1 Compound Heterozygous Mutations in PIDs Patients

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $202,500

## Abstract

Project Summary
The thymus is an organ essential for the development of T cells. There are several congenic
disorders in which the thymus fails to develop, resulting in a severe combined immunodeficiency
in newborns. These include infants with autosomal recessive mutations in FOXN1 or PAX1, and
a subset of newborns with chromosome 22q11.2 deletion syndrome (DiGeorge). For any born
with a complete aplasia of the thymus due to these mutations, an allogeneic thymic stromal tissue
transplant is the clinical approach for restoring some T cell development. Patients with mutations
in FOXN1 present with an athymia along with a now classically described nude phenotype due to
a failure of the hair follicle to penetrant through the dermal layer. As FOXN1 is the master
transcription factor responsible for thymic epithelial cell development, these patients have no T
cells. They are T-B+NK+ SCID/Nude. With the advent of targeted exome and whole genome
sequencing, we report on multiple infants born with compound heterozygous FOXN1 mutations.
This results in a new phenotype of T-B+NK+ with normal hair growth and nail bed extrusion. Since
it is impossible to determine causal effects of the diverse compound heterozygous mutations in
the human cohort, we are genocopying the mutations in mouse models using CRISPR/Cas9.
Several mouse lines studied to date have phenocopied the human T-B+NK+ SCID with normal hair
follicle development. With 15 additional and distinct mutations in human FOXN1 identified, we will
define the functional impact of these mutations on the protein. This will include transcriptional
reporter assays, structural studies, and analyses of cortical and medullary thymic epithelial
development. Our ultimate goal is to understand the differential roles of FOXN1 in thymic versus
keratinocyte development. This will enable clinicians to understand genotype/phenotype
relationships of FOXN1 structure and function to determine when an affected infant requires an
allogeneic thymic tissue transplant.
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## Key facts

- **NIH application ID:** 9851814
- **Project number:** 5R21AI144140-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** NICOLAI Stanislas Cyrille VAN OERS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,500
- **Award type:** 5
- **Project period:** 2019-01-18 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851814

## Citation

> US National Institutes of Health, RePORTER application 9851814, The Functions of Novel FOXN1 Compound Heterozygous Mutations in PIDs Patients (5R21AI144140-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9851814. Licensed CC0.

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