A partial form of recessive STAT1 deficiency in humans

• Published in: The Journal of clinical investigation Vol. 119; no. 6; pp. 1502 - 1514
• Main Authors: Chapgier, Ariane, Kong, Xiao-Fei, Boisson-Dupuis, Stéphanie, Jouanguy, Emmanuelle, Averbuch, Diana, Feinberg, Jacqueline, Zhang, Shen-Ying, Bustamante, Jacinta, Vogt, Guillaume, Lejeune, Julien, Mayola, Eleonore, de Beaucoudrey, Ludovic, Abel, Laurent, Engelhard, Dan, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2009
• Subjects: Alleles; Alternative Splicing - genetics; Amino Acids - genetics; Amino Acids - metabolism; Base Sequence; Biomedical research; Cells, Cultured; Disease; DNA binding proteins; Female; Genes; Genetic aspects; Genetic transcription; Humans; Immune system; Immunodeficiency; Infections; Interferon; Interferons - genetics; Interferons - metabolism; Kinases; Male; Mutation; Mutation - genetics; Pedigree; Physiological aspects; Risk factors; RNA, Messenger - genetics; Siblings; STAT1 Transcription Factor - deficiency; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Viral infections; France; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci37083

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.