title: TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk.
abstract: 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: G743D+R811I 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.
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Lim
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Timo
authors.initials: T
authors.lastname: Hautala
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciancanelli
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Fabien G
authors.initials: FG
authors.lastname: Lafaille
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: William
authors.initials: W
authors.lastname: Dell
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pauwels
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Rönnelid
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Soraya
authors.initials: S
authors.lastname: Boucherit
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Alisan
authors.initials: A
authors.lastname: Yildiran
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Anne
authors.initials: A
authors.lastname: Vergison
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Reina
authors.initials: R
authors.lastname: Roivainen
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.affiliation: Authors' affiliations are listed at the end of the article.
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Authors' affiliations are listed at the end of the article. casanova@rockefeller.edu shzh289@rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Authors' affiliations are listed at the end of the article. casanova@rockefeller.edu shzh289@rockefeller.edu.
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D020803:Encephalitis, Herpes Simplex / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012008:Recurrence; D012307:Risk Factors; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics*
chemical_list: C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3