title: Pseudodominant inheritance in a family with nonautoimmune hypothyroidism due to biallelic DUOX2 mutations.
abstract: OBJECTIVE
  Mutations in the dual oxidase 2 gene (DUOX2) is the most common genetic cause of congenital hypothyroidism (CH) in Japan. All previously described DUOX2 mutation-carrying families have followed autosomal recessive inheritance. We report a nonconsanguineous Japanese family harbouring biallelic DUOX2 mutations, which presented an apparently dominant inheritance of nonautoimmune hypothyroidism.
  
  
  METHODS
  The proband and her two sisters had been diagnosed as having CH on newborn screening and were treated with levothyroxine. Their mother had subclinical hypothyroidism. We sequenced DUOX2 in the proband and her family members. Pathogenicity of the identified novel mutation (p.Y1347C) was verified in vitro.
  
  
  RESULTS
  We found that the proband and her sisters were compound heterozygous for a novel DUOX2 mutation p.Y1347C and a previously reported functional variant p.H678R. Unexpectedly, we found that the mother was homozygous for p.H678R. Expression experiments showed that the p.Y1347C mutant had reduced H2 O2 -producing activity, although there was no significant difference in the level of protein expression or localization, between wild type and p.Y1347C.
  
  
  CONCLUSIONS
  We report a DUOX2 mutation-carrying pedigree presenting pseudodominant inheritance of nonautoimmune hypothyroidism. We speculate that the relatively high frequency of DUOX2 mutations could lead to pseudodominant inheritance in Japan.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Ayuko S
authors.initials: AS
authors.lastname: Suwanai
authors.affiliation: Division of Endocrinology and Metabolism, Aichi Childeren's Health and Medical Center, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamajima
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000483:Alleles; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D000074623:Dual Oxidases; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
chemical_list: D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human