Genetic variations of immunoregulatory genes associated with Rasmussen syndrome

Objective: To elucidate the genetic predisposition of Rasmussen syndrome (RS).

Methods: In 29 Japanese patients, we examined the genome sequences of cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell-death 1 (PDCD1), and T-bet (TBX21) genes by direct Sequencing, and evaluated the significance of SNPs (single nucleotide polymorphism) by comparison with Hap Map data.

Results: In all patients, no disease-causative mutations were found in CTLA4, PDCD1, and T-bet. However, rs231775 SNP in exon 1 of CTLA4 showed significant positive genotypic (p=0.0363) and allelic associations (p=0.0137) with onset of RS compared with Japanese controls, as did rs231779 SNP in intron 1 of CTLA4 (p=0.0467 and 0.0188, respectively). Also, rs2227982 SNP in exon 5 of PDCD1 showed significant positive genotypic and allelic associations with RS (p=0.0145 and 0.0114, respectively). Poor cognitive outcome (IQ below 50) was found in 0% of wild type (C/C), 9% of heterologous (C/T) and 25% of homologous (T/T) genotype of rs2227982. Quadriplegia was found only in homologous (T/T) genotype, and hemiplegia was in heterologous (C/T) and homologous (T/T) genotype of rs2227982. No association between SNPs of T-bet and RS onset was found. Regarding SNPs in promoter regions (rs4794067 and rs17250932) of T-bet, however, IQ below 50 was found in 19% of wild type (T/T) and 0% of heterologous (T/C) genotype of rs4794067, and in 19% of wild type (T/T) and 0% of heterologous (T/C) genotype of rs17250932. Quadriplegic patients were found only in wild-type patients (rs4794067 and rs17250932).

Conclusions: We identified three SNPs (rs231775, rs231779, rs2227982) as some of the SNPs associated with onset of Japanese RS. We need further studies in other populations to confirm these genetic predispositions in RS.

CTLA4; Epilepsy; PDCD1; Rasmussen syndrome; T-bet.