TY - JOUR
T1 - FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans
AU - Du, Qiumei
AU - Huynh, Larry K.
AU - Coskun, Fatma
AU - Molina, Erika
AU - King, Matthew A.
AU - Raj, Prithvi
AU - Khan, Shaheen
AU - Dozmorov, Igor
AU - Seroogy, Christine M.
AU - Wysocki, Christian A.
AU - Padron, Grace T.
AU - Yates, Tyler R.
AU - Louise Markert, M.
AU - Teresa de la Morena, M.
AU - van Oers, Nicolai S.C.
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074379045&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074379045&partnerID=8YFLogxK
U2 - 10.1172/JCI127565
DO - 10.1172/JCI127565
M3 - Article
C2 - 31566583
AN - SCOPUS:85074379045
SN - 0021-9738
VL - 129
SP - 4724
EP - 4738
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -