title: Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone.
abstract: BACKGROUND
  Heterozygous mutations in thyroid hormone receptor-beta (TRbeta) gene are the cause of resistance to thyroid hormone (RTH) in more than 85% of families having the syndrome. In 23% of the families, TRbeta gene mutations occur de novo. Of the 141 families with RTH investigated by us, 21 (15%) had no TRbeta gene mutations detectable by sequencing from genomic DNA (gDNA) or cDNA (non-TR RTH).
  
  
  OBJECTIVE
  The objective of the study was to investigate the genotype of a family with RTH and correlate it to the phenotype.
  
  
  METHODS
  The DNA was isolated from different tissues, and the sequence of the TRbeta gene was determined. Clinical studies involved the administration of incremental doses of T(3).
  
  
  METHODS
  The study was conducted at a referral pediatric endocrinology clinic in Turkey and an academic medical center in the United States.
  
  
  METHODS
  Measurement included markers of thyroid hormone action and sequencing of TRbeta revealing a R338W mutation. Patients and Family: We studied two siblings with short stature, panic disorder, psychosis, and high free iodothyronine concentrations with nonsuppressed TSH and their father with similar thyroid function tests without growth or psychiatric abnormalities.
  
  
  RESULTS
  Direct sequencing of gDNA obtained from the father's leukocytes, buccal mucosa cells, and prostate tissue showed less amplification of the mutant allele (R338W) than the normal allele as confirmed by PCR/restriction fragment length polymorphism analysis. No sequence abnormalities were detected in gDNA from fibroblasts. Similar results were found in mRNA from the leukocytes and fibroblasts. The sensitivity of various tissues to thyroid hormone was not uniform. The progeny had equal amounts of mutant and wild-type gDNA in leukocytes and skin.
  
  
  CONCLUSIONS
  The father has a mosaicism for the R338W mutation as it was present in some cell lineages, including his germline, because it was transferred to his children but not in fibroblasts. This indicates that the mutation occurred de novo in early embryonic life. Here is the first report of mosaicism in RTH. The possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the TRbeta gene.
authors.affiliation: University of Chicago, MC 3090, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Sunee
authors.initials: S
authors.lastname: Mamanasiri
authors.forename: Sena
authors.initials: S
authors.lastname: Yesil
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Tevfik
authors.initials: T
authors.lastname: Demir
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000328:Adult; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009030:Mosaicism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013972:Thyrotropin; D004247:DNA; D013974:Thyroxine