title: Identification of a KEAP1 germline mutation in a family with multinodular goitre.
abstract: BACKGROUND
  The familial clustering of multinodular goitres (MNGs) with a dominant mode of inheritance has been repeatedly reported. Linkage studies have revealed several genetic loci responsible for familial MNG; however, most of the causative variants remain unknown.
  
  
  RESULTS
  Through linkage analysis using single-nucleotide polymorphism markers, we identified a new MNG locus on 19p13.2-q12 in a five-generation Japanese MNG family. Subsequent mutation searches focusing on the candidate 25-Mb region of chromosome 19 identified a heterozygous mutation, c.879_880delinsA, p.Asp294Thr, fs*23, in exon 3 of the KEAP1, which plays a central role in the cytoprotection pathway against oxidative stress. Reverse transcriptase-PCR analysis showed low expression of wild type KEAP1 accompanied by no transcription product of mutant allele in the normal and goitre region of thyroid tissues obtained from the proband. In agreement with previous studies showing that KEAP1 negatively regulates NFE2L2, the NFE2L2 target genes GSTA4 and GCLC were up-regulated in the thyroid tissues of the patient.
  
  
  CONCLUSIONS
  This study identified the first KEAP1 mutation in MNG. The results provide insights into the pathogenesis of goitre which develops in the organ continuously exposed to oxidative stress during hormone synthesis.
authors.affiliation: Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Teshiba
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Tajiri
authors.forename: Kenzo
authors.initials: K
authors.lastname: Sumitomo
authors.forename: Kouji
authors.initials: K
authors.lastname: Masumoto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Taguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005190:Family; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006044:Goiter, Nodular / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D050505:Mutant Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human