RTHα

Resistance to thyroid hormone due to THRA mutation (RTHα): an emerging genetic disease

This page has the ambition to bring all the information currently available to clinicians, in order to facilitate the identification of new cases of this genetic disease (last update Sept 2017). This is important because early detection permits early treatment, preventing adverse neurodevelopmental consequences.

Discovery:

The nuclear receptors of thyroid hormone, TRα1, TRβ1 and TRβ2 are encoded by 2 genes: THRA and THRB (Flamant et al., 2006). While genetic mutations of THRB have been known for a long time in humans, causing a genetic disease now called RTHβ (Refetoff et al., 2014), the discovery of THRA mutations and the associated RTHα disease is more recent (Bochukova et al., 2012). RTHα and RTHβ seem to have similar prevalence, but the diagnostic of RTHα is more difficult. The disease description currently relies on reports of 24 heterozygous patients, corresponding to 13 different mutations of the TRα1 reading frame. RTHα manifests with several features of hypothyroidism without marked reduction in thyroid hormones level (Schoenmakers et al., 2013). It should be stressed that there is at this point no clear distinctive trait or biochemical marker to recognize RTHα. The severity is also quite variable.  

Gene and protein structure:

THRA encodes the TRα1 receptor and a number of other proteins. Alternate codon usage produces p43 (Pessemesse et al., 2011) and p28 (Kalyanaraman et al., 2014), two proteins proposed to be involved in non-genomic response to thyroid hormone. Alternate splicing and alternate promoter usage also produce proteins with unknown functions: TRα2, TRα3, TRΔα1 and TRΔα2 (Flamant and Samarut, 2003). Some THRA mutations also alter the production of these proteins. The possible consequences of altering other proteins than TRα1 are unclear.

TRα1 is a 410AA protein divided into a DNA binding domain and a C-terminal ligand binding domain. The C-terminal helix 12 (AA397-407) of the ligand binding domain plays a central role in coactivator recruitment. The 23 mutations found in the 31 identified patients are in the ligand binding domain. Mutations can either alter T3 binding affinity or coactivator recruitment when found in helix 12.

Diagnostic

Most traits are suggestive of congenital hypothyroidism, while T4 and T3 levels remaining within normal range. However the T4/T3 ratio is often low and reverse T3 being subnormal. If compared to carefully matched controls, these biochemical parameters may be the most reliable marker to suspect RTHα. Most patients have short stature, notably short legs. Several adult patients have large head circumference, with increased thickness of the skull. Skeletal malformations are frequent. Mental retardation varies within a broad range. High anxiety in adults has been reported. Chronic constipation, skin tags and anemia have been frequently observed.   Three patients have been reported to have epileptic seizures. Seven out of 31 cases were classified as autistic patients.

Treatment:

Most patients are currently treated with excess of levothyroxine to overcome resistance. If patients display residual sensitivity to thyroid hormone, this treatment can provide some benefit, as long as heart rate is not increased. Importantly, excess of thyroid hormone could protect young children from irreversible neurodevelopmental defects.

Mouse models have been generated earlier and extensively analyzed (review in (Flamant and Gauthier, 2013). 4 mutations equivalent to RTHα have been created by homologous recombination: R384C (Tinnikov et al., 2002), P398H (Liu et al., 2003), L400R (Quignodon et al., 2007) and PV in which the C-terminus of TRα1 has been replaced by a peptide found in TRβ1 mutant created by a frameshift (Kaneshige et al., 2001).

External links:

Exome Aggregation Consortium (ExAC) last release (0.3, January 2015) 357 THRA rare variants discovered in anonymous patients. Among these, 68 are missense or frameshift mutations in TRα1 reading frame.

OMIM :

 http://omim.org/entry/190120

NCBI:

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

Genome Browser:

genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&position=chr17%3A38214543-38250120

http://www.genecards.org/cgi-bin/carddisp.pl?gene=THRA

Références :

• Bochukova, E., Schoenmakers, N., Agostini, M., Schoenmakers, E., Rajanayagam, O., Keogh, J.M., Henning, E., Reinemund, J., Gevers, E., Sarri, M., et al. (2012). A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 366, 243-249.
• Demir, K., van Gucht, A.L., Buyukinan, M., Catli, G., Ayhan, Y., Nijat Bas, V., Dundar, B., Ozkan, B., Meima, M.E., Edward Visser, W., et al. (2016). Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor Alpha Mutations. J Clin Endocrinol Metab, jc20161404.
• Espiard, S., Savagner, F., Flamant, F., Vlaeminck-Guillem, V., Guyot, R., Munier, M., d'Herbomez, M., Bourguet, W., Pinto, G., Rose, C., et al.  (2015). A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. J Clin Endocrinol Metab 100, 2841-2848.
• Flamant, F., Baxter, J.D., Forrest, D., Refetoff, S., Samuels, H., Scanlan, T.S., Vennstrom, B., and Samarut, J. (2006). International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 58, 705-711.
• Flamant, F., and Gauthier, K. (2013). Thyroid hormone receptors: the challenge of elucidating isotype-specific functions and cell-specific response. Biochim Biophys Acta 1830, 3900-3907.
• Flamant, F., and Samarut, J. (2003). Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 14, 85-90.
• Kalikiri, M.K., Mamidala, M.P., Rao, A.N., and Rajesh, V. (2017). Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients. Autism research : official journal of the International Society for Autism Research.
• Kalyanaraman, H., Schwappacher, R., Joshua, J., Zhuang, S., Scott, B.T., Klos, M., Casteel, D.E., Frangos, J.A., Dillmann, W., Boss, G.R., et al. (2014). Nongenomic thyroid hormone signaling occurs through a plasma membrane-localized receptor. Science signaling 7, ra48.
• Kaneshige, M., Suzuki, H., Kaneshige, K., Cheng, J., Wimbrow, H., Barlow, C., Willingham, M.C., and Cheng, S. (2001). A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci U S A 98, 15095-15100.
• Liu, Y.Y., Schultz, J.J., and Brent, G.A. (2003). A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem 278, 38913-38920.
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• Pessemesse, L., Schlernitzauer, A., Sar, C., Levin, J., Grandemange, S., Seyer, P., Favier, F.B., Kaminski, S., Cabello, G., Wrutniak-Cabello, C., et al. (2011). Depletion of the p43 mitochondrial T3 receptor in mice affects skeletal muscle development and activity. Faseb J.
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• Tinnikov, A., Nordstrom, K., Thoren, P., Kindblom, J.M., Malin, S., Rozell, B., Adams, M., Rajanayagam, O., Pettersson, S., Ohlsson, C., et al. (2002). Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. Embo J 21, 5079-5087.
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