title: A Novel Germline Mutation of KEAP1 (R483H) Associated with a Non-Toxic Multinodular Goiter.
abstract: BACKGROUND
  A germline mutation ofKEAP1gene was reported as a novel genetic abnormality associated with familial multinodular goiter. That report was limited, and the pathogenic features were not well established.
  
  
  METHODS
  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 with nodules obtained from four unrelated patients with multinodular goiters.
  
  
  CONCLUSIONS
  A novel germline mutation (R483H) ofKEAP1gene was associated with the development of a non-toxic multinodular goiter.
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Eijun
authors.initials: E
authors.lastname: Nishihara
authors.affiliation: Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University , Mibu , Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hishinuma
authors.affiliation: Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University , Mibu , Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kogai
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Takada
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Hirokawa
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukata
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yabuta
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amino
authors.affiliation: Center for Excellence in Thyroid Care, Kuma Hospital , Kobe , Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Miyauchi
keywords: Graves’ disease; KEAP1 germline mutation; NRF2 expression; familial goiter; multinodular goiter