PLoS ONE (Jan 2013)

Variations of the UNC13D gene in patients with autoimmune lymphoproliferative syndrome.

  • Maurizio Aricò,
  • Elena Boggio,
  • Valentina Cetica,
  • Matteo Melensi,
  • Elisabetta Orilieri,
  • Nausicaa Clemente,
  • Giuseppe Cappellano,
  • Sara Buttini,
  • Maria Felicia Soluri,
  • Cristoforo Comi,
  • Carlo Dufour,
  • Daniela Pende,
  • Irma Dianzani,
  • Steven R Ellis,
  • Sara Pagliano,
  • Stefania Marcenaro,
  • Ugo Ramenghi,
  • Annalisa Chiocchetti,
  • Umberto Dianzani

DOI
https://doi.org/10.1371/journal.pone.0068045
Journal volume & issue
Vol. 8, no. 7
p. e68045

Abstract

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Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development.