Fatal combined immunodeficiency associated with heterozygous mutation in STAT1.
BACKGROUND
Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations).


OBJECTIVE
To define the molecular basis of progressive combined immunodeficiency in a group of patients with fatal infections.


METHODS
We studied a group of unrelated patients who displayed an unusual progressive form of combined immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed.


RESULTS
Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections.


CONCLUSIONS
These findings show that some heterozygous aberrations of STAT1 can be associated with progressive combined immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.
Division of Immunology and Allergy, the Canadian Centre for Primary Immunodeficiency, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Nigel
N
Sharfe
Canada-Israel Immunodeficiency Research Alliance, Toronto, Ontario, Canada; Kaplan Medical Center, Hebrew University, Rehovot, Israel.
Amit
A
Nahum
Division of Immunology and Allergy, the Canadian Centre for Primary Immunodeficiency, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Andrea
A
Newell
Division of Immunology and Allergy, the Canadian Centre for Primary Immunodeficiency, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Harjit
H
Dadi
Division of Pathology, Department of Pediatric Laboratory Medicine, Toronto, Ontario, Canada.
Bo
B
Ngan
Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Sergio L
SL
Pereira
Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jo-Anne
JA
Herbrick
Division of Immunology and Allergy, the Canadian Centre for Primary Immunodeficiency, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Canada; Canada-Israel Immunodeficiency Research Alliance, Toronto, Ontario, Canada. Electronic address: chaim.roifman@sickkids.ca.
Chaim M
CM
Roifman
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D019014:fas Receptor / Q000032:analysis
C491901:FAS protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019014:fas Receptor
Combined immunodeficiency; STAT1; mutation