Anti-THRA monoclonal antibody, clone 2440

Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TR alpha 1, and Alzheimer's disease (AD) risk. We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI] = 1.71 [0.99-2.95] p = 0.06). We extended our finding to three other independent AD case control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI] = 1.42 [1.03-1.96], p = 0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR = 1.19 [0.97-1.45], p = 0.10). The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded. (C) 2009 Elsevier Inc. All rights reserved.

Background: Thyroid hormone acts via receptor subtypes (TR alpha 1, TR beta 1, TR beta 2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels. Scope of review: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner. Major conclusions: Mutations in human TR alpha 1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. General significance: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling. (C) 2013 Elsevier B.V. All rights reserved.