Human Molecular Genetics Advance Access first published online on October 31, 2009
This version [Corrected Proof] published online on November 16, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp507
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A novel form of cell type-specific partial IFN-
R1 deficiency caused by a germ line mutation of the IFNGR1 initiation codon
,*1 Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA, 2 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, U550, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France, 3 University Paris Descartes, Necker Medical School, 75015 Paris, France, 4 French-Chinese Laboratory of Genetics and Life Science, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, 200025 Shanghai, People's Republic of China, 5 The Traffic, Signaling and Delivery Laboratory, UMR144 Curie Centre National de la Recherche Scientifique, Institut Curie, 75005 Paris, France, 6 Hospital for Children and Adolescents, Helsinki University and University Hospital, Helsinki, Finland, 7 Pediatric Research Center, Tampere University and University Hospital, Tampere, Finland, 8 Department of Pediatrics, Kuopio University and University Hospital, Kuopio, Finland and 9 Pediatric Immunology-Hematology Unit, Necker Hospital, 75015 Paris, France
* To whom correspondence should be addressed. Tel: +1 2123277331; Fax: +1 2123277330; Email: jean-laurent.casanova{at}rockefeller.edu
Received September 1, 2009; Accepted October 29, 2009
IFN-
R1 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial diseases, and includes two forms of complete recessive deficiency, with or without cell surface expression, and two forms of partial deficiency, dominant or recessive. We report here a novel form of partial and recessive Interferon receptor 1 (IFN-R1) deficiency, which is almost as severe as complete deficiency. The patient is homozygous for a mutation of the initiation codon (M1K). No detectable expression and function of IFN-R1 were found in the patient's fibroblasts. However, IFN-R1 expression was found to be impaired, but not abolished, on the EBV-transformed B cells, which could respond weakly to IFN-. The mechanism underlying this weak expression involves leaky translation initiation at both non-AUG codons and the third AUG codon at position 19. It results in the residual expression of IFN-R1 protein of normal molecular weight and function. The residual IFN- signaling documented in this novel form of partial IFN-R1 deficiency was not ubiquitous and was milder than that seen in other forms of partial IFN-R1 deficiency, accounting for the more severe clinical phenotype of the patient, which was almost as severe as that of patients with complete deficiency.
These authors contributed equally to this work.