Biallelic p.R2223H mutation in the thyroglobulin gene causes thyroglobulin retention and severe hypothyroidism with subsequent development of thyroid carcinoma

Abstract

Context: Dyshormonogenesis due to genetic defect in thyroglobulin (Tg) synthesis and secretion can lead to congenital hypothyroidism. Objectives: The aim of the study was to analyze the TG gene for the presence of mutations and to study the underlying mechanisms leading to dyshormonogenesis. Cases: Two siblings aged 25 and 31 yr presented with recurrent goitrous hypothyroidism with undetectable serum Tg. The older sibling was diagnosed with follicular variant of papillary thyroid carcinoma (FVPTC) at age 21 and metastatic FVPTC 8 yr later. Methods: The entire coding region of TG gene was sequenced. BRAF, RAS, and P53 mutations or PAX8/PPAR-γ rearrangement were screened in the FVPTC. Tg expression was studied by immunohistochemistry. Results: Biallelic c.6725G>A(p.R2223H)andc.6396C>T(p.S2113L) sequence variationsweredetected in both patients and monoallelic variations in their family members. The c.6396C>T (p.S2113L) sequence variation was found in14%of 100 population controls, whereas c.6725G>Avariation was not present in the controls. Two previously reported polymorphisms (c.2200T>G and c.3082A>G) were present in all the family members. Strong cytoplasmic immunostaining of Tg was observed in the hyperplasticthyroidepithelial cellsandweakornostaining inthefollicularlumen.Cytoplasmicstaining was localized in the endoplasmic reticulum. Reduced staining was found in the FVPTC. Neither RAS, BRAF, or P53 gene mutation nor a PAX8/PPAR-γrearrangement was detected in the tumor tissue. Conclusions: Biallelic c.6725G>A (p.R2223H) mutation causes Tg retention in the endoplasmic reticulum, resulting in dyshormonogenesis. Prolonged TSH stimulation may promote malignant transformation and development of thyroid cancer. The c.6396C>T (p.S2113L) is a novel polymorphism. Copyright © 2010 by The Endocrine Society.