SYSTEMATIC ANALYSIS OF THYROGLOBULIN MUTATIONS FOUND IN PATIENTS WITH HYPOTHYROIDISM AND IN THE GENOME AGGREGATION DATABASE.

GOMES PIO, MAURICIO; SIFFO, SOFÍA; ADROVER, EZEQUIELA; MOLINA, MARICEL F.; SHEPS, KAREN G.; CITTERIO, CINTIA E.; RIVOLTA, CARINA M.; TARGOVNIK , HÉCTOR M.

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica.; 2018

Sociedad Argentina de Investigación Clínica

TG is a large glycosylated protein secreted by the thyrocytes into the follicular lumen by exocytosis and it plays an essential role in the process of thyroid hormone synthesis. The human TG gene is a single copy gene of 270 kb long that maps on chromosome 8q24.2-8q24.3 (chr8: 133,879,203-134,147,147; GRCh37/hg19 assembly) and contains an 8,453 nucleotides in the coding sequence divided into 48 exons. The human TG mRNA encodes a polypeptide chain of 2,767 amino acids. In the present work, we include the analysis of 51 patients from 33 unrelated families with TG mutations identified in our present (p.R296*/c.3001+5G>A, p.C1281Y/c.5686+1G>T) and previous studies. All patients underwent clinical and biochemical evaluation. Sanger sequencing as well as bioinformatics analysis were per formed. Our observation shows that mutations in both TG alleles were found in 29 families (9 as homozygote and 20 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. 29 different mutations were identified, 34 of the 102 TG alleles encoded the change p.R296*. Additionally, we describe the TG mutation analysis in the Genome Aggregation Database (gnomAD). This website to the present spans 123,136 exome sequences and 15,496 whole-genome sequences from unrelated individuals sequenced as part of various disease-specific and population genetic studies. In total, 346 clearly pathogenic TG variants were described, 61 nonsense mutations, 226 splice site mutations (acceptor site [AG], 14; donor site [GT], 31; exonic splice region, 28; intronic splice region, 153) and 59 frameshifts (insertion, 14; deletion 45). The most frequent mutation that causes a premature stop is p.R296* (96 of 277,236 alleles, all heterozygous). In conclusion, the identification and characterization of TG mutations is undoubtedly a valuable approach to study the TG structure/function relations and also provides an important tool for clinical diagnosis and genetic counseling.