AUTHOR=Nishihara Eijun , Hishinuma Akira , Kogai Takahiko , Takada Nami , Hirokawa Mitsuyoshi , Fukata Shuji , Ito Mitsuru , Yabuta Tomonori , Nishikawa Mitsushige , Nakamura Hirotoshi , Amino Nobuyuki , Miyauchi Akira 

TITLE=A Novel Germline Mutation of KEAP1 (R483H) Associated with a Non-Toxic Multinodular Goiter

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 7 - 2016

YEAR=2016

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2016.00131

DOI=10.3389/fendo.2016.00131

ISSN=1664-2392

ABSTRACT=Background: A germline mutation of KEAP1 gene was reported as a novel genetic abnormality associated with familial multinodular goiter. That report was limited, and the pathogenic features were not well established.
Patient Findings: We report a 47-year-old Japanese woman who presented with hyperthyroidism and a large multinodular goiter. The family history was notable for a paternal history of goiter. Graves’ disease was diagnosed based on positive TRAb, but scintiscan imaging showed that the patient’s radioiodine uptake was restricted in the non-nodular areas, indicating largely cold nodules. A total thyroidectomy was performed. The resected thyroid tissue weighed 209 g, and subsequent pathological findings were benign. The patient had a germline heterozygous KEAP1 mutation, c. 1448 G>A, resulting in an amino acid substitution (p.R483H). A next-generation sequencing analysis covering all known genes associated with multinodular goiter showed no additional germline mutation. The nuclear accumulation of NRF2, a protein associated with KEAP1, was shown at much higher rates in the patient’s nodules compared to nodules obtained from four unrelated patients with multinodular goiters.
Conclusions: A novel germline mutation (R483H) of KEAP1 gene was associated with the development of a nontoxic multinodular goiter.