Genetic disorders of thyroid development, hormone biosynthesis and signalling

Abstract

Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action. K E Y W O R D S congenital hypothyroidism, thyroid dysgenesis, thyroid hormone receptors, thyroid hormone resistance, thyroid hormones 1 | DISORDERS OF THYROID HORMONE (TH) DEVELOPMENT AND BIOSYNTHESIS 1.1 | Background Primary congenital hypothyroidism (CH) is traditionally subdivided into thyroid dysgenesis (TD), failure of normal thyroid development due to thyroid ectopy, athyreosis or hypoplasia and dyshormonogenesis (DH), inadequate TH biosynthesis despite a normally-sited, often goitrous thyroid. Monogenic causes of TD are rare, occurring in <5% affected cases whereas DH is usually attributable to pathogenic variants affecting known components of the TH biosynthesis pathway. 1 1.2 | Thyroid dysgenesis Monogenic causes of TD predominantly involve pathogenic variants in key thyroidal transcription factors which define developing thyroid

GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors

“…Interaction of TSH with the TSH receptor (TSHR), a G-protein-coupled receptor, causes activation of several protein kinase pathways that subsequently lead to increased transcription of several genes critical for TH biosynthesis, including the sodium–iodide symporter ( NIS ; SLC5A5 ), dual oxidase 2 ( DUOX2 ), thyroglobulin ( TG ), thyroid peroxidase ( TPO ), and pendrin ( PDS ; SLC26A4 ) [ 3 , 4 ]. Impairments in TH biosynthesis lead to thyroid dyshormonogenesis, one type of congenital hypothyroidism (CH) [ 5 – 9 ].…”

The Spectrum of Endocrine Pathology

“…Dyshormonogenesis is associated with alterations in genes involved in hormone synthesis: SLCA5, DEHAL1, DUOX2, DUOXA2, SCL6A4, TPO, Tg [5]. Mutations in a thyroid hormone transporter monocarboxylate transporter 8 (MCT8) reduce intracellular bioavailability of TH, and thyroid hormone resistance can be due to mutations in thyroid hormone receptors [6]. The lack of feedback suppression in patients with dyshormonogenesis or reduced thyroid hormone transport and action causes elevated TSH that may result in goiter.…”

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism

“…Congenital hypothyroidism (CH) is a de ciency in the formation of thyroid hormones by the thyroid gland due to environmental or genetic causes, characterized by high levels of thyroid-stimulating hormone (TSH) and low levels of thyroid hormone (TH), T 4 and T 3 [1][2][3][4][5]. CH is the most frequent inherited neonatal endocrine pathology, with an incidence of 1 in 1,500 to 1 in 4,000 live births, with frequent ethnic variations.…”

“…The main known genetic causes of primary CH are deleterious variants in genes encoding proteins involved in the different steps of thyroid hormone biosynthesis (thyroid dyshormonogenesis (TDH)) or defects in genes related to thyroid gland development (dysembryogenesis or thyroid dysgenesis) [1,[3][4][5]. TDH usualy arise due to variants in Solute Carrier Family 5 Member 5 (SLC5A5, encoding NIS), Solute Carrier Family 26 Member 4 (SLC26A4, encoding pendrin), Solute Carrier Family 26 Member 7 (SLC26A7), Thyroid Peroxidase (TPO), Dual Oxidase 1 (DUOX1), DUOX Maturation Factor 1 (DUOXA1), Dual Oxidase 2 (DUOX2), DUOX Maturation Factor 2 (DUOXA2), Iodotyrosine Deiodinase (IYD) and Thyroglobulin (TG) genes [1,[3][4][5]. TDH due to variants of the TG gene has an estimated incidence of 1 in 67,000 to 1 in 100,000 newborns and showed an autosomal recessive inheritance pattern.…”