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FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.

Publication ,  Journal Article
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 ...
Published in: J Clin Invest
November 1, 2019

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2019

Volume

129

Issue

11

Start / End Page

4724 / 4738

Location

United States

Related Subject Headings

  • Thymus Gland
  • Severe Combined Immunodeficiency
  • Protein Domains
  • Mutation
  • Mice, Nude
  • Mice
  • Male
  • Immunology
  • Humans
  • Heterozygote
 

Citation

APA
Chicago
ICMJE
MLA
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Du, Q., Huynh, L. K., Coskun, F., Molina, E., King, M. A., Raj, P., … van Oers, N. S. (2019). FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest, 129(11), 4724–4738. https://doi.org/10.1172/JCI127565
Du, Qiumei, Larry K. Huynh, Fatma Coskun, Erika Molina, Matthew A. King, Prithvi Raj, Shaheen Khan, et al. “FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.J Clin Invest 129, no. 11 (November 1, 2019): 4724–38. https://doi.org/10.1172/JCI127565.
Du Q, Huynh LK, Coskun F, Molina E, King MA, Raj P, et al. FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest. 2019 Nov 1;129(11):4724–38.
Du, Qiumei, et al. “FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.J Clin Invest, vol. 129, no. 11, Nov. 2019, pp. 4724–38. Pubmed, doi:10.1172/JCI127565.
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. FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest. 2019 Nov 1;129(11):4724–4738.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2019

Volume

129

Issue

11

Start / End Page

4724 / 4738

Location

United States

Related Subject Headings

  • Thymus Gland
  • Severe Combined Immunodeficiency
  • Protein Domains
  • Mutation
  • Mice, Nude
  • Mice
  • Male
  • Immunology
  • Humans
  • Heterozygote