FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with T–/loB+NK+ SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations. To understand the basis of this phenotype and the effects of the mutations on FOXN1, we generated mice using CRISPR-Cas9 technology to genocopy mutations in 1 of the patients. The mice with the Foxn1 compound heterozygous mutations had thymic hypoplasia, causing a T–B+NK+ SCID phenotype, whereas the hair and nails of these mice were normal. Characterization of the functional changes due to the Foxn1 mutations revealed a 5–amino acid segment at the end of the DNA-binding domain essential for the development of TECs but not keratinocytes. The transcriptional activity of this Foxn1 mutant was partly retained, indicating a region that specifies TEC functions. Analysis of an additional 9 FOXN1 mutations identified in multiple unrelated patients revealed distinct functional consequences contingent on the impact of the mutation on the DNA-binding and transactivation domains of FOXN1.

Original languageEnglish (US)
Pages (from-to)4724-4738
Number of pages15
JournalJournal of Clinical Investigation
Issue number11
StatePublished - Nov 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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