PERSONAL DE APOYO
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SYSTEMATIC ANALYSIS OF THYROGLOBULIN MUTATIONS FOUND IN PATIENTS WITH HYPOTHYROIDISM AND IN THE GENOME AGGREGATION DATABASE.
MAURICIO GOMES PIO; SOFIA SIFFO; EZEQUIELA ADROVER
Congreso; LXIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2018
the follicular lumen by exocytosis and it plays an essential role inthe process of thyroid hormone synthesis. The human TG gene is asingle 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 dividedinto 48 exons. The human TG mRNA encodes a polypeptide chainof 2,767 amino acids.In the present work, we include the analysis of 51 patients from33 unrelated families with TG mutations identified in our present(p.R296*/c.3001+5G>A, p.C1281Y/c.5686+1G>T) and previousstudies. All patients underwent clinical and biochemical evaluation.Sanger sequencing as well as bioinformatics analysis were perwere found in 29 families (9 as homozygote and 20 as heterozygotecompound), whereas in the remaining four families only one mutatedallele was detected. 29 different mutations were identified, 34 ofthe 102 TG alleles encoded the change p.R296*. Additionally, wedescribe the TG mutation analysis in the Genome Aggregation Database(gnomAD). This website to the present spans 123,136 exomesequences and 15,496 whole-genome sequences from unrelatedindividuals sequenced as part of various disease-specific and populationgenetic studies. In total, 346 clearly pathogenic TG variantswere 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; deletion45). The most frequent mutation that causes a premature stop isp.R296* (96 of 277,236 alleles, all heterozygous).In conclusion, the identification and characterization of TG mutationsis undoubtedly a valuable approach to study the TG structure/function relations and also provides an important tool for clinical diagnosisand genetic counseling.