| First Author | Du Q | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 11 | Pages | 4724-4738 |
| PubMed ID | 31566583 | Mgi Jnum | J:280961 |
| Mgi Id | MGI:6370350 | Doi | 10.1172/JCI127565 |
| Citation | Du Q, et al. (2019) FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest 129(11):4724-4738 |
| abstractText | 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. |
