FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Du, Q; Huynh, LK; Coskun, F; Molina, E; King, MA; Raj, P; Khan, S; Dozmorov, I; Seroogy, CM; Wysocki, CA; Padron, GT; Yates, TR; Markert, ML; de la Morena, MT; van Oers, NS

Published Date

  • November 1, 2019

Published In

Volume / Issue

  • 129 / 11

Start / End Page

  • 4724 - 4738

PubMed ID

  • 31566583

Pubmed Central ID

  • PMC6819092

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI127565


  • eng

Conference Location

  • United States