A partial form of recessive STAT1 deficiency in humans.
Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Laboratory of Human Genetics of Infectious Diseases, Necker Faculty, INSERM U550, Paris, France.
Ariane
A
Chapgier
Xiao-Fei
XF
Kong
Stéphanie
S
Boisson-Dupuis
Emmanuelle
E
Jouanguy
Diana
D
Averbuch
Jacqueline
J
Feinberg
Shen-Ying
SY
Zhang
Jacinta
J
Bustamante
Guillaume
G
Vogt
Julien
J
Lejeune
Eleonore
E
Mayola
Ludovic
L
de Beaucoudrey
Laurent
L
Abel
Dan
D
Engelhard
Jean-Laurent
JL
Casanova
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D035781:Siblings
D000596:Amino Acids; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007372:Interferons