Your browser doesn't support javascript.
loading
The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.
Siffo, Sofia; Gomes Pio, Mauricio; Martínez, Elena Bueno; Lachlan, Katherine; Walker, Joanna; Weill, Jacques; González-Sarmiento, Rogelio; Rivolta, Carina M; Targovnik, Héctor M.
Afiliação
  • Siffo S; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Buenos Aires, Argentina.
  • Gomes Pio M; CONICET-Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina.
  • Martínez EB; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Buenos Aires, Argentina.
  • Lachlan K; CONICET-Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina.
  • Walker J; Unidad de Medicina Molecular-Departamento de Medicina, IBMCC and IBSAL. Universidad de Salamanca-CSIC, Salamanca, España.
  • Weill J; Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, SO16 5YA, Southampton, UK.
  • González-Sarmiento R; Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Cosham, PO6 3LY, Portsmouth, UK.
  • Rivolta CM; Clinique de Pédiatrie, Hôpital Jeanne de Flandre, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
  • Targovnik HM; Unidad de Medicina Molecular-Departamento de Medicina, IBMCC and IBSAL. Universidad de Salamanca-CSIC, Salamanca, España.
Endocrine ; 80(1): 47-53, 2023 04.
Article em En | MEDLINE | ID: mdl-36547798
Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify and functionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanisms responsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with marked alteration of TG synthesis were studied. The two families were previously analysed in our laboratory, only one deleterious allele, 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 variants of 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, amino acid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently express p.Pro2232Leu in a full-length rat TG cDNA clone and confirmed that this point variant was sufficient to cause intracellular retention 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 importance of altered TG folding as a consequence of missense variants located in the ChEL domain of TG.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipotireoidismo Congênito / Bócio Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Endocrine Assunto da revista: ENDOCRINOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipotireoidismo Congênito / Bócio Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Endocrine Assunto da revista: ENDOCRINOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos