title: An intronic SNP in the thyroid hormone receptor β gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor β2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone.
abstract: BACKGROUND
  The syndrome of resistance to thyroid hormone (RTH) is caused by mutations in the thyroid hormone receptor β gene (THRB). The syndrome varies from asymptomatic to diffuse hypothyroidism, to pituitary-selective resistance with predominance of hyperthyroid signs and symptoms. The wide spectrum of clinical presentation is not completely attributable to specific THRB mutations. The THRB gene encodes two main isoforms, TR β1 which is widely distributed, and TR β2, whose expression is limited to the cochlea, retina, hypothalamus, and pituitary. Recent data demonstrated that in mice an intron enhancer region plays a critical role in the pituitary expression of the β2 isoform of the receptor. We thus hypothesized that polymorphisms in the human homologous region could modulate the pituitary expression of the mutated gene contributing to the clinical presentation of RTH.
  
  
  METHODS
  Screening and in vitro characterization of polymorphisms of the intron enhancer region of the THRB gene in the index case of pituitary-selective RTH.
  
  
  RESULTS
  The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in cis with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the THRB gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR β2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele.
  
  
  CONCLUSIONS
  The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, NIDDK-NIH Bethesda, Maryland, USA.
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Alberobello
authors.forename: Valentina
authors.initials: V
authors.lastname: Congedo
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Craig
authors.initials: C
authors.lastname: Cochran
authors.forename: Monica C
authors.initials: MC
authors.lastname: Skarulis
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Celi
mesh_terms: D000328:Adult; D002648:Child; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones