Thyroid hormones, generalized resistance to thyroid hormones (thyroid hormone resistance Generalized -GTHR-) - Gen THRB

The generalized resistance to thyroid hormones (gThr) is a disorder characterized by a variable hyporesponsiveness to L-triiodothyronine (T3) with a marked and persistent increase of T3 and circulating free thyroxine (tetraiodothyronine, T4) in association with TSH levels normal or slightly higher. Associated signs and symptoms may include gThr goiter, hypothyroidism and hyperthyroidism, short stature, increased susceptibility to infections, tachycardia, hearing loss, delayed bone maturation disorders and attention deficit hyperactivity disorder (ADHD).

If resistance to thyroid hormones equally affects the pituitary and periphery increased T3 and T4 with normal TSH or slightly higher occurs. This is the classic pattern of the disease, but there are variations. If resistance to thyroid hormones is more pronounced in the hypophysis than in the periphery TSH, T3 and T4 are all high, with hyperthyroidism. Conversely, if resistance is heightened in the periphery it may not be compensated by the high concentrations of T4 and T3 and result in hypothyroidism.

Receptors of thyroid hormone (TR) are transcription factors that mediate ligand-dependent biological activities of T3. They are encoded by genes THRA, located on the long arm of chromosome 17 (17q11.2) and THRB, located on the short arm of chromosome 3 (3p24.2). The splicing (cutting and sealing) of the primary transcripts alternative results in the formation of four T3 binding proteins (?1, ?2, ?3, ?1) and two proteins that do not bind to T3 (?2 ?3 and).

THRA1 and THRB1 are the major proteins. THRA1 is expressed primarily in the brain, heart and bones while THRB1 more abundant in liver, kidney and thyroid. THRB2 expression is limited to the internal pituitary gland, hypothalamus, retina and THRB3 ear and is expressed mainly in the heart and kidney.

In 90% of individuals with thyroid hormone resistance mutations they have been detected in the THRB gene. Until now more than 125 have been found anomalies in different regions, particularly amino acid substitutions and missense mutations. They occur in the last 4 of its 10 exons, which are the encoding the hinge region of the receptor and the ligand binding domain, causing a decrease in T3 binding and / or impairment of transactivation. They not detected in any case THRA mutations in the gene.

This process can be inherited in an autosomal dominant or autosomal recessive pattern. An autosomal dominant inheritance means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. Meanwhile, an autosomal recessive pattern, implies that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with generalized resistance to thyroid hormone (gThr), by complete PCR amplification of the exons of the gene THRB, and subsequent sequencing. It is recommended to begin the study by exons 7, 8, 9 and 10 where the mutations identified to date, with possible reduction of time and cost are located. If not found the mutation in this region, it offers the ability to complete the study by the remains of exons.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).