Screening And Research The TG Mutation In Patients With Congenital Hypothyroidism

Congenital hypothyroidism（CH）is a common endocrinedisease in childhood,which may lead to slow growth and mental retardation in children.Previous studies illustrated that many mutations in genes associated with thyroxine synthesis are associated with the development of CH.Thyroglobulin（TG）is the matrix of thyroid hormone synthesis,and the mutations of the TG gene may effects the secretion of the thyroid hormone.Therefore,it is one of the important causes of CH.In this study,130 CH patients and 100 controls from Xi’an were selected as the subjects.The exons of TG gene of CH patients were detected by the high-throughput sequencing method to research the mutation spectrum of TG mutations in Northwest of China and analyze the molecular mechanism of TG gene mutation during CH pathogenesis.In 130 patients with CH,a total of 24 TG mutations that could lead to CH were found,including 4 nonsense mutations,3 splice mutations and 17 missense mutations.8 of these are novel mutations,including c.4641₄641delQ c.2060₂060delG,c.2864₂864delA,c.6840₆843delTTGT,c.3139+2T>C,c.3634-1delQ c.1514G>A,c.7182C>G The result of computational biology illustrated 12 mutations of our study maybe the harmful mutations of TG.The other 12 mutations were predicted to be likely benign for CH.Sequence of TG protein was compared with Bos taturus,Sus scrofa,Pongo abelii,Mus musculus,Rattus norvegicus.Result illustrated the mutations p.Arg1202Cys,p.Pro2236Leu,p.Ile2394Met,p.Arg2585Trp are in the conserved regions of the protein,and the mutations p.Pro2236Leu,p.Ile2394Met,p.Arg2585Trp are in the functional domains.Using protein homology modeling method,the analysis of its three-dimensional structure suggested that the mutations c.6707C>T（p.Pro2236Leu）and c.7753C>T（p.Arg2585Trp）caused change of the protein.Finally,according to the guidelines and criteria of pathogenicity of ACMQ the pathogenic of the 24 mutations were classified.The results showed that 7 of them were mutations that could be pathogenic,including 4 frameshift mutations,3 splice mutations and 5 missense mutations,7 missense mutations are uncertain significance,while the other 10 mutations are benign or likely benign.The results of this study illustrated the Northwestern China CH patients,frequency of TG mutations in CH patients was 23%,of which 86.7%heterozygous mutations,13.3%were compound heterozygous mutations.In this study,two patients with complex heterozygous except for c.7182C>G/c.3035C>T and c.2560C>T/c.1919A>G were severe CH patients with goiter,but some patients who did not carry TG mutations also showed severe CH,therefore there may be other CH-related gene mutations,need to be further explored.In conclusion,in this study,used high-throughput sequencing to research the mutations of TG gene in CH patients in Northwestern region,and expanded the mutation spectrum of TG gene.At the same time,the relationship between TG mutations and clinical phenotype was established.Therefore,it may provide theoretical basis for further research the pathogenesis of CH.