Familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by perforin 1 (PRF1),
is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first
2 years of life and has a poor prognosis. Late onset of FHL2 has been sporadically
reported, and the mechanism is largely unknown. A newly diagnosed FHL2 patient was
detected to have compound mutations in both PRF1 alleles and positive Epstein-Barr
virus (EBV) infection. Her brother carried the same mutations and EBV infection status
but kept healthy. To search the potential unknown mechanisms, we performed whole-exome
sequencing analysis. The patient and her asymptomatic brother carried the same heterozygous
missense (c.916G>A) and frameshift mutation (c.65delC) in PRF1. Germline mutation
analysis demonstrated that only the proband was exclusively detected with a homozygous
missense mutation (S1006L) in the PCDH18 gene, whereas others were found to have a
heterozygous mutation (S1006L) of PCDH18. The calculated stability (free energy) changes
showed that the mutation of PCDH18 mainly destabilized the protein structure. Furthermore,
the mutation (S1006L) could lessen the PCDH18-induced inhibition of target cell activation
and reduce the apoptosis of T lymphocytes. This study is the first to perform whole-exome
sequencing analysis to search the potential “second-hit” mechanism that underlies
the onset of FHL2. A novel type of compound heterozygous mutation has been found in
PRF1. The detection of the homozygous germline mutation in PCDH18 strongly argues
that the presence of a “second” germline mutation besides the PRF1 gene might be potentially
an important mechanism for triggering the onset of FHL2.
Abbreviations:
APC (antigen-presenting cell), CTLs (cytotoxic T cells), EBV (Epstein-Barr virus), FHL (familial hemophagocytic lymphohistiocytosis), H&E (hematoxylin and eosin), HLH (hemophagocytic lymphohistiocytosis), PBMCs (peripheral blood mononuclear cells), PBS (phosphate balanced solution), PRF1 (perforin 1), rIL-2 (recombinant interleukin 2), RT-PCR (reverse transcription–polymerase chain reaction), SE (standard error)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 14, 2015
Accepted:
December 3,
2015
Received in revised form:
November 22,
2015
Received:
July 22,
2015
Footnotes
Lili Gao and Xiao Dang contributed equally to this work.
Identification
Copyright
© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
