In 2 unrelated French children with immunodeficiency-83 manifest as herpes simplex encephalitis (IMD83; 613002), Zhang et al. (2007) identified heterozygosity for a c.1660C-T transition in the TLR3 gene, resulting in a pro554-to-ser (P554S) substitution. Pro554 is highly conserved in a leucine-rich region of TLR3 in fish and mammals. The mutations occurred on different TLR3 haplotypes in the children, indicating that they represent independent mutational events. Some relatives in each kindred who were heterozygous for the mutation lacked a history of HSE but were HSV-1 seropositive. The mutation was not identified in 1,581 unrelated healthy individuals. Functional expression studies showed that the P554S mutation resulted in loss of interferon production when stimulated, consistent with a loss of function; the mutation also showed a dominant-negative effect.
In a 19-year-old man (patient P), born of unrelated Polish parents, with herpes simplex encephalitis at 8 years of age, Guo et al. (2011) identified compound heterozygous missense mutations in the TLR3 gene: a c.1660C-T transition in exon 4, resulting in a pro554-to-ser (P554S) substitution in the ectodomain, and a c.2236G-T transversion in exon 4, resulting in a glu746-to-ter (E746X; 603029.0003) substitution in the linker region, predicted to result in a truncated protein without proper translation of the TIR domain. The E746X mutation was not found in 2,082 control chromosomes. Both mutations were found in the patient's leukocytes and fibroblasts, and the mutations segregated with the disorder in the family. The patient also carried a homozygous TLR3 polymorphism (L412F; 603029.0002). Expression of the mutant alleles into a TLR3-deficient fibrosarcoma cell line showed that the P554S allele encoded a truncated form of TLR3 with a molecular mass of about 80 kD (the wildtype protein has a molecular mass of about 130 kD). The E746X mutant protein showed abnormal glycosylation of the C-terminal end, and some of the protein was mislocated in the cell. Neither P554S nor E746X was able to rescue the deficits in interferon production in response to poly(I:C) when transfected into TLR3-null cells, consistent with a loss of function. Patient fibroblasts showed complete lack of beta- and gamma-interferon production in response to poly(I:C) and lack of interferon production, as well as increased viral replication and cell death, when infected in vitro with HSV-1 and VSV; however, they showed normal interferon response when infected with multiple other viruses. Moreover, patient leukocytes showed normal interferon response to poly(I:C) and when exposed to multiple viruses, including HSV-1 and VSV. The findings suggested that TLR3 is vital for protective immunity to primary HSV-1 infection in the central nervous system, but is largely redundant for systemic host defense, which also explains the lack of disseminated disease in this patient.
Lim et al. (2019) identified a heterozygous P554S mutation in 2 unrelated children with IMD83 manifest as severe pneumonitis due to infection with influenza A (IAV). These findings expanded the phenotype associated with TLR3 mutations to include other virus susceptibilities and tissue manifestations.
