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Transl Res. 2016 Apr;170:26-39. doi: 10.1016/j.trsl.2015.12.004. Epub 2015 Dec 15.

Search for the potential "second-hit" mechanism underlying the onset of familial hemophagocytic lymphohistiocytosis type 2 by whole-exome sequencing analysis.

Author information

1
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
2
BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, People's Republic of China; BGI-Shenzhen, Shenzhen, People's Republic of China.
3
BGI-Shenzhen, Shenzhen, People's Republic of China.
4
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: jiawei@tjh.tjmu.edu.cn.
5
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: jfzhou@tjh.tjmu.edu.cn.

Abstract

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.

PMID:
26739415
DOI:
10.1016/j.trsl.2015.12.004
[Indexed for MEDLINE]

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