A Novel p.E311K Mutation of Thyroid Receptor Beta Gene in Resistance to Thyroid Hormone Syndrome, Inherited in Autosomal Recessive Trait

Abstract

Resistance to thyroid hormone (RTH) syndrome is caused by mutations in THRB gene and is inherited mainly as an autosomal dominant trait with dominant negative effect. Most of up-to-now described RTH cases were heterozygous. We studied a 19-year-old woman presenting severe mental impairment, hyperkinetic behavior, learning disability, hearing loss, tachycardia, goiter, strabismus, nystagmus, and normal stature. The laboratory findings revealed elevated TSH, T3, and T4 serum levels. Her parents were healthy with normal serum level of TSH, fT3, and fT4. Sequence based prediction of a substitution was analyzed by SDM, PolPhen, and SNAP software whereas structural visualizations were performed in UCSF Chimera. We found a novel mutation in THRB gene in position 1216 (G to A transition, codon 311) resulting in novel Glu-311-Lys (p.E311K) substitution, homozygous in proband presenting with severe symptoms of RTH and heterozygous in both of her healthy parents, thus suggesting autosomal recessive mode of inheritance. p.E311K substitution was not found in 50 healthy, unrelated individuals. p.E311K was shown to be deleterious by SDM, PolPhen, and SNAP software. Structural visualizations of mutated protein performed by UCSF Chimera software disclosed a loss of hydrogen bonds between E311, R383, and R429 along with abnormal residue-residue contact between K311 and L377. This is a very rare case of a homozygous mutation in a patient with severe symptoms of RTH and lack of symptoms in both heterozygous parents. Although, computational analyses have provided the evidence that p.E311K substitution may affect THRB function, lack of dominant negative effect typical for THRB mutations could not be explained by structure-based modeling. Further in vitro analysis is required to assess the functional consequences of this substitution.

• References

• 1 Chatterjee VK, Nagaya T, Madison LD, Datta S, Rentoumis A, Jameson JL. J Clin Invest 1991; 87: 1977-1984
• 2 Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK. J Clin Invest 1994; 94: 506-515
• 3 Collingwood TN, Wagner R, Matthews CH, Clifton-Bligh RJ, Gurnell M, Rajanayagam O, Agostini M, Fletterick RJ, Beck-Peccoz P, Reinhardt W, Binder G, Ranke MB, Hermus A, Hesch RD, Lazarus J, Newrick P, Parfitt V, Raggatt P, de Zegher F, Chatterjee VK. EMBO J 1998; 17: 4760-4770
• 4 Takeda K, Sakurai A, DeGroot LJ, Refetoff S. J Clin Endocrinol Metab 1992; 74: 49-55
• 5 Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. J Comput Chem 2004; 25: 1605-1612
• 6 Sandler B, Baxter J, Fletterick R In: Beck-Peccoz P. (ed.). Dordrecht: Kluwer Academic Publishers; 2004: 35-57
• 7 Marimuthu A, Feng W, Tagami T, Nguyen H, Jameson JL, Fletterick RJ, Baxter JD, West BL. Mol Endocrinol 2002; 16: 271-286
• 8 Machado DS, Sabet A, Santiago LA, Sidhaye AR, Chiamolera MI, Ortiga-Carvalho TM, Wondisford FE. Proc Natl Acad Sci USA 2009; 106: 9441-9446
• 9 Narumi S, Cho H, Tamada I, Kozu Y, Tsuchiya T, Nagai T, Hasegawa T. Clinical Pediatric Endocrinol 2010; 19: 91-99
• 10 Frank-Raue K, Lorenz A, Haag C, Höppner W, Boll HU, Knorr D, Hentze S, Raue F., Eur J. Endocrinol 2004; 150: 819-823
• 11 Ono S, Schwartz ID, Mueller OT, Root AW, Usala SJ, Bercu BB. J Clin Endocrinol Metab 1991; 73: 990-994
• 12 Florkowski CM, Brownlie BE, Croxson MS, Manning P, Farrand S, Smith G, Potter HC, George PM. Intern Med J 2006; 36: 738-741
• 13 Cheng SY. Trends Endocrinol Metab 2005; 16: 176-182