The p.Pro2232Leu variant in the Chel domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.

BUENO MARTÍNEZ, ELENA; SIFFO, SOFÍA; WEILL, JACQUES; LACHLAN, KATHERINE; TARGOVNIK , HÉCTOR M; GONZALEZ-SARMIENTO, ROGELIO; GOMES PIO, MAURICIO; WALKER, JOANNA; RIVOLTA, CARINA M.

ENDOCRINE

HUMANA PRESS INC

Lugar: Oregon; Año: 2022

0969-711X

Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroidhormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrumof congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify andfunctionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanismsresponsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with markedalteration of TG synthesis were studied. The two families were previously analysed in our laboratory, only one deleteriousallele, in each one, was detected after sequencing the TG gene (c.2359 C > T [p.Arg787*], c.5560 G > T [p.Glu1854*]).These findings were confirmed in the present studies by Next-Generation Sequencing. The single nucleotide coding variantsof the TG gene were then analyzed to predict the possible variant causing the disease. The p.Pro2232Leu (c.6695 C > T),identified in both families, showing a low frequency population in gnomAD v2.1.1 database and protein homology, aminoacid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently expressp.Pro2232Leu in a full-length rat TG cDNA clone and confirmed that this point variant was sufficient to cause intracellularretention of mutant TG in HEK293T cells. Consequently, each family carried a compound heterozygous for p.Arg787*/p.Pro2232Leu or p.Glu1854*/p.Pro2232Leu variants. In conclusion, our results confirm the pathophysiological importanceof altered TG folding as a consequence of missense variants located in the ChEL domain of TG.Keywords Congenital hypothyroidism ● Thyroglobulin gene ● ChEL domain ● Compound heterozygous variants ●Intracellular retention