The Pathogenicity Of RYR3 Gene Mutation In Infantile Spasms

Objective: To analyze the characteristic of the biology,inheritance and clinical symptoms in 4 patients with RYR3 gene mutation,and to explore the pathogenic potential of RYR3 mutation in patients with infantile spasms.Methods: We collected the clinical information of 4 patients who are diagnosed with infantile spasms accompanied by RYR3 gene mutations in Child's Hospital of Chongqing Medical University.We use sanger sequencing to verify the source of mutation and homology modeling methods to analyze the changes of three-dimensional structure of protein,RT-q PCR to detect the expression level of target protein in 2 patients,one pair of parents and 10 normal children.Results:(1)four different mutation site are found(c.8400-5 c > T,c.8137-3 T > c,c.17 A > G,c.30 c > A),two of them(c.8400-5 c > T,c.8137-3 T > c)were splicing mutation across introns of the DNA sequences and another two(c.17 A > G,c.30 c > A)were occurred in coding regions.4 point mutations are all inherited from their parents.2 patients have a common mutation(c.8400-5 c > T).3 patients are found withheterozygous mutations,1 patient is found with compound heterozygous mutations.(2)We found that c.8400-5c >T mutation occurred in coil of the protein through the homologous modeling methods and no changes of the3 D structure of the protein compared with wild protein.(3)The detection of the expression level of target protein between the 2 patients with heterozygous mutations and normal children show no regularly changes.(4)The patient with RYR3 compound heterozygous mutations developed severe clinical symptoms,including uncontrolled seizures and global developmental delay.3 patients with heterozygous mutations become seizure-free after received antiepileptic drug treatment and developed mild to moderate developmental delay.Conclusion: There's no obvious correlation between genotype and phenotype in infantile spasm with RYR3 gene mutation.