Endocrine Abstracts (2017) 49 OC4.3 | DOI: 10.1530/endoabs.49.OC4.3

A novel variant in the SERPINA7 gene causing partial TBG deficiency in a women and two male siblings: molecular and protein structural analysis

Cristiane Lima1, Andressa Maciel1, Sarah Caixeta Cardoso1, Matheus Andrade1, Vinicius Cunha1, Lucas Bleicher2, Juliana mazzeu3 & Adriana Lofrano-Porto1

1University of Brasília, Faculty of Health Sciences, Molecular Pharmacology Laboratory, Brasilia, DF, Brazil; 2Federal University of Minas Gerais, Department of Bichemistry and Imunology, Belo Horizonte, MG, Brazil; 3Univeristy of Brasilia, Faculty of Medicine, Medical Genetics Laboratory, Brasilia, DF, Brazil.

Background: Thyroxine-binding globulin (TBG) is the major human thyroid hormone transport protein. It is encoded by the SERPINA7 gene, located on the long arm of the X chromosome (Xq22.2). Inherited TBG abnormalities result in complete (TBG-CD) or partial (TBG-PD) TBG deficiency. We performed a comprehensive molecular analysis of the SERPINA7 gene in a Brazilian family with TBG-PD.

Methods: Genomic DNA was extracted from the female proband, her father, dizygotic twin sister and two brothers, and the coding region of the SERPINA7 gene was sequenced. The proband’s X-chromosome inactivation pattern was evaluated by methylation analysis using the human androgen receptor (AR) gene, located next to SERPINA7 (Xq11.2). Structural analysis of the Serpin protein family was performed using PFSTATS, and was also used to map equivalent positions in all human homologs. Molecular modeling was done as described by Feyfant et al.

Results and Discussion: A novel missense mutation in the SERPINA7 gene (p.R35W; c.163C>T) was found in heterozygosity in the proband and in hemizygosity in her brothers. They presented low serum levels of total T4, total T3 and TBG, compatible with TBG-PD. The proband expressed an X-chromosome inactivation ratio of 20:80. The substitution of an arginine by a tryptophan is predicted to disrupt the protein surface and main electrostatic interactions. The conservation and correlation patterns showed that tryptophans are extremely rare (0.1%) in this position, and there is no significant (P<10-10) pairwise.

Conclusion: We report a new variant of the SERPINA7 gene associated with TBG-PD in three siblings. The proband’s X-chromosome inactivation pattern may have accounted for the rare phenotypic expression in a heterozygous woman. The hydrophobic nature of the mutant is predicted to create an apolar patch at the protein surface, which would be significantly exposed to the solvent, and result in protein aggregation and/or misfolding with consequent thyroxin transport defect.

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