TLR3 deficiency in herpes simplex encephalitis: High allelic heterogeneity and recurrence risk

Hye Kyung Lim, Mikko Seppänen, Timo Hautala, Michael J. Ciancanelli, Yuval Itan, Fabien G. Lafaille, William Dell, Lazaro Lorenzo, Minji Byun, Elodie Pauwels, Ylva Rönnelid, Xin Cai, Soraya Boucherit, Emmanuelle Jouanguy, Anders Paetau, Pierre Lebon, Flore Rozenberg, Marc Tardieu, Laurent Abel, Alisan YildiranAnne Vergison, Reina Roivainen, Amos Etzioni, Pentti J. Tienari, Jean Laurent Casanova, Shen Ying Zhang

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency ,0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D1R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients. Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.

Original languageEnglish
Pages (from-to)1888-1897
Number of pages10
Issue number21
StatePublished - 1 Nov 2014
Externally publishedYes


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