RTHα

Resistance to thyroid hormone due to TRα1 mutation (RTHα)

 

This page gathers all the information available on this rare genetic disease discovered in 2012 and will be regularly updated. The aim is to favor the discovery of new patients.

 RTHα
From Tylki-Szymanska, A., et al.  2015 J Med Genet.

 Genetic cause: RTHα is due to mutations of the THRA gene. THRA encodes several proteins, including TRα1, one of the two types of nuclear receptor of thyroid hormone. Only 24 heterozygous patients with RTHα have been reported (see table 1). This contrasts with the hundreds of known RTHβ patients, carrying mutations of THRB, which encodes the other TRβ1/2 receptors. However mining of anonymous exome databases suggest that the prevalence of RTHα and RTHβ are similar.  Reported TRα1 mutations alter either the affinity for T3, or the structure of C-terminal helix (AA 397-410) which is required for TRα1 to interact with transcription coactivators.  Mutations in the DNA binding domain have not yet been reported. The mutations which only alter ligand binding affinity do not fully inactivate the receptors, and usually cause a mild phenotype.

Diagnostic: RTHα is very difficult to recognize due to phenotype variability and absence of specific markers. Patients display several traits suggestive of congenital hypothyroidism, but the circulating levels of T4 and T3 remain within normal range (T4/T3 ratio being usually low).  The most recurrent symptoms are moderate mental retardation and dysmorphic or retarded bone growth, but exceptions have already been observed among the few known patients. The most recent review provides an extensive description of the syndrome (Moran C, Chatterjee K.(2015)  Best Pract Res Clin Endocrinol Metab. 2015 29(4):647-57). It should be stressed that unexpected presentations cannot be rule out, given the small number of reported cases.

 Treatment: Patients often display residual sensitivity to thyroid hormones, due to heterozygote status and presence of TRβ1/2. Supplementation with excess of thyroid hormone is thus sometimes beneficial. In that respect early detection of mutation is important, as earlier treatment could prevent neurodevelopmental defects.

Mouse models: THRA is highly conserved among vertebrates. Four “knock-in” mouse models have been produced and extensively studied several years before RTHα discovery in humans. A number of additional knock-out models are also available.

Table I: Human mutations (last update June 2016)

Type of mutation

DNA

Protein

Position

 

Carriers  

Total number

13

13

10

 

24

missense

 

D211G

211

Van Gucht Abstract 2014

1

missense

GCG to GTG

A263V

263

Moran, C., et al.  2014   

3

missense

?

A263S

263

Demir et al. 2016

5

missense

1075C>G

N359Y

359

Espiard et al 2015

1

frameshift

?

C380fs387X

380

Demir et al. 2016

1

frameshift

1144delG

A382PfsX7

382

Moran, C., et al.  2013   

1

missense

?

R384C

384

Yuen, R. K., et al.  2015   

1

missense

?

 R384H

384

Demir et al. 2016

2

missense

1176C>A,

C392X

392

Tylki-Szymanska, A., et al.  2015  

1

frameshift

1191 ins T

F397fs406X

397

van Mullem, A. A., et al.  2012

2

missense

1193C>G

P398R

398

Tylki-Szymanska, A., et al.  2015  

1

missense

1207G>T

E403X

403

Bochukova, E., et al.  2012    

1

missense

1207G>T

E403X

403

Tylki-Szymanska, A., et al.  2015  

1

missense

1207G>A

E403K

403

Tylki-Szymanska, A., et al.  2015  

1

missense

1207G>A

E403K

403

Tylki-Szymanska, A., et al.  2015  

2

 

Table 2: Mouse models (last update Sept 2015)

Mice name

Type of mutation

Protein

Position

Reference

 

missense

R384C

384

Tinnikov, A., 2002  Embo J 21(19):5079-87.

TRαPV

Copied from TRβPV

393 PHRTLPPFVLGSVRGLD

393

Kaneshige, M., 2001 PNAS 98(26):15095-100

 

missense

P398H

398

Liu, Y. Y., 2003  J Biol Chem 278(40):38913-20

TRαAMI

missense

L400R

400

Quignodon, L., 2007  Mol Endocrinol 21(10):2350-60.

 

Bibliographie: This is to our knowledge a complete list of publications of RTHα patients, including reviews (last update June 2016). If we missed one please contact us.

2016

    • Demir K, van Gucht AL, Büyükinan M, Çatlı G, Ayhan Y, Nijat Bas V, Dündar B, Özkan B, Meima ME, Edward Visser W, Peeters RP, Visser TJ. (2016) Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor Alpha Mutations. J Clin Endocrinol Metab.  May 4:jc20161404
    • Tang Y, Yu M, Lian X. 2016 Resistance to thyroid hormone α, revelation of basic study to clinical consequences. J Pediatr Endocrinol Metab. May 1;29(5):52. R11-2eview

 

2015

    • Espiard, S., F. Savagner, F. Flamant, V. Vlaeminck-Guillem, R. Guyot, M. Munier, M. d'Herbomez, W. Bourguet, G. Pinto, C. Rose, P. Rodien, and J. L. Wemeau. 2015. A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. J Clin Endocrinol Metab 100:2841-2848.
    • Tylki-Szymanska, A., R. Acuna-Hidalgo, M. Krajewska-Walasek, A. Lecka-Ambroziak, M. Steehouwer, C. Gilissen, H. G. Brunner, A. Jurecka, A. Rozdzynska-Swiatkowska, A. Hoischen, and K. H. Chrzanowska. 2015. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (THRA). J Med Genet 52:312-316.
    • Moran, C., and K. Chatterjee. 2015. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab 29:647-657.
    • Yuen, R. K., B. Thiruvahindrapuram, D. Merico, S. Walker, K. Tammimies, N. Hoang, C. Chrysler, T. Nalpathamkalam, G. Pellecchia, Y. Liu, M. J. Gazzellone, L. D'Abate, E. Deneault, J. L. Howe, R. S. Liu, A. Thompson, M. Zarrei, M. Uddin, C. R. Marshall, R. H. Ring, L. Zwaigenbaum, P. N. Ray, R. Weksberg, M. T. Carter, B. A. Fernandez, W. Roberts, P. Szatmari, and S. W. Scherer. 2015. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med 21:185-191.
    • Moran, C., M. Agostini, W. E. Visser, E. Schoenmakers, N. Schoenmakers, A. C. Offiah, K. Poole, O. Rajanayagam, G. Lyons, D. Halsall, M. Gurnell, D. Chrysis, A. Efthymiadou, C. Buchanan, S. Aylwin, and K. K. Chatterjee. 2014. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha1 and TRalpha2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol 2:619-626.

 

2014

    • Refetoff, S., J. H. Bassett, P. Beck-Peccoz, J. Bernal, G. Brent, K. Chatterjee, L. J. De Groot, A. M. Dumitrescu, J. L. Jameson, P. A. Kopp, Y. Murata, L. Persani, J. Samarut, R. E. Weiss, G. R. Williams, and P. M. Yen. 2014. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab 99:768-770.
    • van Gucht, A., N. Zwaveling-Soonawala, M. E. Meima, W. E. Visser, T. J. Visser, R. P. Peeters, and A. S. van Trotsenburg. 2014. "Effects of early LT4 treatment in a patient with a mutation in TRα1/α2." European Thyroid Association, Santiago de Compostela, Spain.
    • van Mullem, A. A., T. J. Visser, and R. P. Peeters. 2014. Clinical Consequences of Mutations in Thyroid Hormone Receptor-alpha1. Eur Thyroid J 3:17-24.

 

2013

    • Moran, C., N. Schoenmakers, M. Agostini, E. Schoenmakers, A. Offiah, A. Kydd, G. Kahaly, S. Mohr-Kahaly, O. Rajanayagam, G. Lyons, N. Wareham, D. Halsall, M. Dattani, S. Hughes, M. Gurnell, S. M. Park, and K. Chatterjee. 2013. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. J Clin Endocrinol Metab 98:4254-4261.
    • Schoenmakers, N., C. Moran, R. P. Peeters, T. Visser, M. Gurnell, and K. Chatterjee. 2013. Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. Biochim Biophys Acta 1830:4004-4008.
    • van Mullem, A. A., D. Chrysis, A. Eythimiadou, E. Chroni, A. Tsatsoulis, Y. B. de Rijke, W. E. Visser, T. J. Visser, and R. P. Peeters. 2013. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRalpha1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab 98:3029-3038.

 

2012

    • van Mullem, A., R. van Heerebeek, D. Chrysis, E. Visser, M. Medici, M. Andrikoula, A. Tsatsoulis, R. Peeters, and T. J. Visser. 2012. Clinical phenotype and mutant TRalpha1. N Engl J Med 366:1451-1453.
    • Bochukova, E., N. Schoenmakers, M. Agostini, E. Schoenmakers, O. Rajanayagam, J. M. Keogh, E. Henning, J. Reinemund, E. Gevers, M. Sarri, K. Downes, A. Offiah, A. Albanese, D. Halsall, J. W. Schwabe, M. Bain, K. Lindley, F. Muntoni, F. Vargha-Khadem, M. Dattani, I. S. Farooqi, M. Gurnell, and K. Chatterjee. 2012. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 366:243-249.

 

External links:

Exome database: http://exac.broadinstitute.org/about

http://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=thra&x=0&y=0

Gene information:  http://www.ncbi.nlm.nih.gov/gene/7067

Online Mendelian Inheritance in Man:

http://omim.org/entry/190120