Novel mutational mechanism in the thyroglobulin gene: Imperfect DNA inversion as a cause for hereditary hypothyroidism.

CITTERIO CINTIA E; ROSSETTI LILIANA C; SOUCHON PIERRE F; CECILIA MORALES; MATHILDE THOUVARD-VIPREY; ANNE S. SALMON-MUSIAL; PIERRE L.A. MAURAN; MARTINE DOCO-FENZY; ROGELIO GONZÁLEZ-SARMIENTO; CARINA M. RIVOLTA; CARLOS D. DE BRASI; TARGOVNIK, HECTOR M.

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2013 vol. 381 p. 220 - 229

0303-7207

The objective of this study was to perform genetic analysis in three brothers of Turkish origin born from consanguineus parents and affected by congenital hypothyroidism, goiter and low levels of serum TG. The combination of sequencing of DNA, PCR mapping, quantitative real-time PCR, inverse-PCR (I-PCR), multiplex PCR and bioinformatics analysis were used in order to detect TG mutations. We demonstrated that the three affected siblings are homozygous for a DNA inversion of 16,962 bp in the TG gene associated with two deleted regions at both sides of the inversion limits. The inversion region includes the first 9 bp of exon 48, 1015 bp of intron 47, 191 bp of exon 47, 1523 bp of intron 46, 135 bp of exon 46 and the last 14,089 bp of intron 45. The proximal deletion corresponds to 27 bp of TG intron 45, while the distal deletion spans the last 230 bp of TG exon 48 and the first 588 bp of intergenic region downstream TG end. The parents were heterozygous carriers of the complex rearrangement. In conclusion, a novel large imperfect DNA inversion within the TG gene was identified by the strategy of I-PCR. This aberration was not detectable by normal sequencing of the exons and exon/intron boundaries. Remarkably, the finding represents the first description of a TG deficiency disease caused by a DNA inversion.