Variations of the Perforin Gene in Patients With Type 1 Diabetes

  1. Umberto Dianzani1
  1. 1Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, A. Avogadro University of Eastern Piedmont, Novara, Italy
  2. 2Pediatric Haematology-Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  3. 3Immunohaematology and Transfusion Center, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  4. 4Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  5. 5Department of Pediatric Sciences, Gaslini Institute-IRCCS, University of Genoa, Genoa, Italy
  6. 6Department of Pediatrics, University of Turin, Turin, Italy
  7. 7Department of Internal Medicine, University of Turin, Turin, Italy
  1. Address correspondence and reprint requests to Umberto Dianzani, IRCAD-Department of Medical Sciences, Via Solaroli, 17, I-28100, Novara, Italy. E-mail: umberto.dianzani{at}


OBJECTIVE—Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes.

RESEARCH DESIGN AND METHODS—We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects.

RESULTS—In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 6.68 [95% CI 1.83–7.48]). Sequencing of the entire coding region detected one novel mutation in one patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes–predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A.

CONCLUSIONS—These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.

  • Received July 10, 2007.
  • Accepted January 9, 2008.
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  1. Diabetes vol. 57 no. 4 1078-1083
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