Structural insights revealed by two novel THRB mutations

Autor(es)

Cardoso, Ludmilla Ferreira ^[1] ; de Carvalho Melo, Maria Clara ^[2] ; Takahashi, Mirian Hideco ^[3] ; Nascimento, Alessandro Silva ^[4] ; Chiamolera, Maria Izabel ^[2] ; Zanini Maciel, Lea Maria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Med, Lab Mol & Translat Endocrinol, Escola Paulista Med, Sao Paulo, SP - Brazil

^[3] Univ Estadual Maringa, Dept Med, Maringa, Parana - Brazil

^[4] Univ Sao Paulo, Sao Carlos Inst Phys, Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ENDOCRINE; v. 68, n. 1 JAN 2020.
• Citações Web of Science: 0

Resumo

Purpose Among the inheritable forms of impaired sensitivity to thyroid hormone, resistance to thyroid hormone (RTH) due to mutations in the thyroid hormone receptor beta gene (THRB) is the first and best known described defect, revealing a wide phenotypic variability with an incompletely understood physiopathology. The objective of this study was to evaluate two novel mutations in THRB, N331H and L346R, in an attempt to provide a rational understanding of the harmful effects caused by them. Methods The mutations of two patients with RTH beta were reproduced for analysis of gene transactivation by dual-luciferase reporter assay, and for molecular modeling for crystallography-based structural assessment. Serum measurements of TSH and FT4 were performed to compare the thyrotrophic resistance to thyroid hormone between RTH beta patients and controls. Results Both mutants showed impaired gene transactivation, with greater damage in L346R. Molecular modeling suggested that the damage occurring in N331H is primarily due to reduced strength of the hydrogen bonds that stabilize T3 in its ligand-binding cavity (LBC), whereas in L346R, the damage is more marked and is mainly due to changes in hydrophobicity and molecular volume inside the LBC. Hormonal dosages indicated that the L346R mutant exhibited greater thyrotrophic resistance than N331H. Conclusions This study provides a rational understanding of the effects of mutations, indicating deleterious structural changes in the LBC in both THR, and discloses that not only the position of the mutation but, notably, the nature of the amino acid exchange, has a cardinal role in the functional damage of the receptor. (AU)

• Processo FAPESP: 13/04210-0 - Estudo funcional de dois receptores mutantes do hormônio tireoidiano em pacientes com a síndrome de resistência ao hormônio tireoidiano
• Beneficiário: Léa Maria Zanini Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Regular