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1 Resistance to Thyroid Hormone - emerging definition of a disorder of thyroid 2 hormone action 3 4 Carla Moran and Krishna Chatterjee 5 6 University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC, Institute of 7 Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom 8 9 Abbreviated title: RTH. 10 11 Key terms: Resistance to Thyroid Hormone, dominant negative inhibition; THRA mutation 12 13 Disclosure statement: The authors have nothing to disclose 14 15 Word Count: text (1651); figures 1 16 17 Address for correspondence and reprint requests: 18 V Krishna K Chatterjee, University of Cambridge, Metabolic Research Laboratories, Wellcome Trust- 19 MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge, CB2 20 0QQ. Tel: (44)-1223-336842; Fax: (44)-1223-330598; Email: [email protected] 21 22 Funding: Our research is supported by funding from the Wellcome Trust (095564/Z/11/Z to KC) and 23 National Institute for Health Research Cambridge Biomedical Research Centre (CM, KC). 24 25 26 27 1 28 Thyroid hormones (TH) act via nuclear receptors, encoded by separate genes (THRA, THRB), with 29 differing tissue distributions (TR1: central nervous system, myocardium, skeletal muscle, 30 gastrointestinal tract; TR1: liver, kidney; TR2: hypothalamus, pituitary, cochlea, retina). 31 Alternative splicing of THRA generates a variant, non TH-binding, protein (TR2), with a divergent 32 carboxyterminal domain, whose function is not understood (1). 33 Resistance to thyroid hormone (RTH), usually due to heterozygous mutations in THRB, is 34 characterised by raised T4 and T3 levels, non-suppressed TSH and a variable phenotype 35 encompassing both hyperthyroid (e.g. failure to thrive, raised metabolic rate, tachycardia, low bone 36 density, anxiety) and hypothyroid (e.g. dyslipidaemia) features (2). Consonant with its dominant 37 mode of inheritance, dominant negative inhibition of wild type receptor function by mutant TR is 38 central to the pathogenesis of this disorder (3). Although TR and proteins exhibit marked 39 aminoacid sequence similarity, such that introduction of a receptor mutation causing RTH into the 40 murine TR gene is associated with an abnormal phenotype (e.g. growth retardation, locomotor 41 abnormalities) (4), the homologous human disorder (Resistance to Thyroid Hormone , RTH), 42 eluded discovery for over a decade probably because it was not associated with a readily-recognisable 43 diagnostic signature. 44 RTH, due to a highly deleterious mutation (E403X), truncating the carboxyterminal region of TR1, 45 was first identified in a six yr old girl with hypothyroid features (e.g. skeletal dysplasia with growth 46 retardation, neurodevelopmental delay, constipation) in selected target tissues, but associated with 47 near-normal (borderline low or normal T4, borderline high or normal T3, normal TSH) thyroid 48 function tests (5). Subsequently, further childhood plus adult male and female cases, harbouring 49 frameshift/premature stop mutations also involving the carboxyterminus of TR1 were found, with 50 recognition of additional, potentially pathognomonic, features (macrocephaly, anaemia, dysmorphic, 51 facies) (6,7). Indeed, recognition of a distinct, shared, phenotype encompassing macrocephaly and 52 dysmorphic features in a single clinic, led to the identification of a further five cases with similar, 53 carboxyterminal TR1 mutations (8). Where functionally characterised, these TR1 mutants 54 exhibited negligible hormone binding and functional activity, with failure to dissociate from 2 55 transcriptional corepressor and recruit coactivator proteins – properties that are highly analogous to 56 those of dominant negative TRmutants in RTH (3). From these reports, a biochemical signature for 57 RTH also seemed to emerge; although TH levels could be in the normal range, a computed T4/T3 58 ratio or reverse T3 levels (where ascertained) were subnormal (5,8,9). Following this, a missense 59 THRA mutation (A263V), located in a receptor region common to both TR1 and TR2 proteins, was 60 identified in three members of a family with similar clinical (growth and developmental retardation, 61 constipation, macrocephaly) features. The A263V TR1 mutant showed partial loss-of-function, 62 being transcriptionally impaired at low TH concentrations in vitro, with reversal of this at higher T3 63 levels. It was tempting to speculate that such partial preservation of mutant TR1 function accounted 64 for a milder phenotype in this family. However, the possibility that thyroxine treatment of these cases 65 since early childhood had also contributed to amelioration of the phenotype, could not be discounted. 66 Concordant with no measurable gain- or loss-of-function of A263V mutant TR2 compared with its 67 normal counterpart, no added phenotypes attributable to mutated TR2, could be discerned in these 68 cases (10). In contrast, some unusual added clinical features (micrognathia, clavicular agenesis, 69 metacarpal fusion and syndactyly of digits, hyperparathyroidism, chronic diarrhoea) were reported in 70 an adult female harbouring a different mutation (N359Y), common to both TR1 and TR2 proteins 71 (11). 72 In this context, the report by Demir and colleagues in the current issue of JCEM (12), describing three 73 different THRA mutations (C380fs387X, R384H, A263S) in 10 RTH patients from 3 different 74 families, together with associated clinical features, clarifies several aspects of this disorder. The 75 authors were able to discern a gradation in phenotype associated with different genotypes: a child, 76 harbouring a highly deleterious mutation (C380fs387X) involving the carboxyterminus of TR1, is 77 growth retarded with cognitive and motor deficits that result in severe handicap; moderate cognitive 78 deficit, motor abnormalities and growth retardation in infancy but less evident in adulthood, were 79 recorded in a child and mother with a partial loss-of-function mutation (R384H) in TR1; in a large 80 family, harbouring A263S mutant TR1 with slightly impaired function, mild growth retardation and 3 81 slight developmental delay in childhood culminated in average/low-average adult IQ, with 82 constipation being a relatively conserved clinical feature. 83 The A263S mutation in THRA reported by Demir et al, as well as another RTH-associated mutation 84 (D211G) reported recently by the same group, also involve the TR2 protein (12,13). No added 85 phenotypic characteristics were observed in nine affected individuals harbouring one or other of these 86 mutated residues. Accordingly, it is conceivable that the unusual skeletal and other abnormalities 87 unique to the patient with the N359Y THRA mutation, are attributable to a defect in another pathway; 88 although whole exome sequencing was undertaken in this case, a pathogenic abnormality (for 89 example in a non-coding gene region) has not been excluded (11). Alternatively, as depicted when 90 RTH mutations reported hitherto are mapped on the crystal structure of TR1, the Asparagine to 91 Tyrosine change at codon 359 (N359Y), involves a residue that is in an unusual location in the 92 receptor protein compared to the position of other RTH-associated mutations (Figure 2); therefore, 93 the possibility of the N359Y substitution inducing a specific functional alteration in the receptor that 94 is linked to unique, additional phenotypes, cannot be discounted. 95 With the identification of a more functionally diverse repertoire of TR1 mutations, a specific 96 biochemical signature for RTH seems less clearcut. Specifically, in some cases, particularly 97 associated with mild TR mutations (e.g. A263S, D211G), normal reverse T3 levels have been 98 documented (12,13). The T4/T3 or T3/rT3 ratio remains abnormal in most cases, overlapping 99 minimally with values in unaffected family members (12), but this abnormal thyroid function test 100 pattern is a recognised feature of other disorders (e.g. MCT8 deficiency) (14); likewise, although mild 101 anaemia is almost universal in RTH, this parameter is unhelpfully nonspecific. Studies in a 102 transgenic model of RTH raised the possibility of circulating trace element (selenium) levels having 103 diagnostic utility (15), but did not translate readily into the human context (7). In RTH, even subtle 104 TR mutants exhibit impaired negative feedback regulation of hypothalamo-pituitary target genes 105 (TRH, TSH) (16), reflected in pathognomonic, raised, TH levels. It has been suggested that a 106 combination of raised type 1 deiodinase and reduced type 3 deiodinase enzyme activities accounts for 107 thyroid biochemical abnormalities in RTH17); whether another TH metabolite that reflects such 4 108 altered deiodinase activity more consistently or a biomarker associated with another universally 109 dysregulated pathway in this disorder, can be identified, remains to be seen. 110 With the estimated prevalence of RTH being ~1 in 40,000, with over 160 different TR mutations 111 recorded hitherto, it is likely that RTH is more common, but underdiagnosed. Both maternal and 112 paternal transmission of TR mutations has now been recorded in several families (6, 8, 10, 12, 13), 113 suggesting that, unlike in a murine transgenic model (18), fertility in either gender is not unduly 114 compromised. However, screening for THRA defects based on current, documented, phenotypes may 115 artificially enrich for identification of particular TR mutations (e.g. involving the carboxyterminal 116 receptor region). Supporting this notion, whole exome sequencing (WES), identified a TR variant 117 (R384C), known to be pathogenic in transgenic mice (4), associated with autism spectrum disorder – 118 an unexpected phenotype (19). Indeed, interrogation of exome databases (e.g. ExAC; 119 http://exac.broadinstitute.org/gene/ENSG00000126351) reveals many rare, nonsyonymous THRA 120 variants including several in TR1 predicted to be damaging, based either on homology to known 121 RTH mutations or structural modelling. However, in the absence of definitive diagnostic criteria 122 (clinical, biochemical) for RTH, it may be necessary to develop functional assays to assess the 123 putative pathogenicity of receptor variants, as has been done for PPARG variants identified in WES of 124 type 2 diabetes cohorts (20). TR mutations causing RTH cluster within three regions of its hormone 125 binding domain and, as illustrated in Figure 1, many RTH-associated TR mutations have TR 126 counterparts, involving the same aminoacids, which localise to these clusters. As the repertoire of 127 RTH-associated TR mutations grows, it will be interesting to see whether they also localise to 128 particular receptor regions. One functional constraint on RTH-associated TR mutations is 129 preservation of the ability to exert dominant negative activity, such that receptor regions mediating 130 functions (DNA binding, interaction with corepressor and RXR) that are required for such activity are 131 devoid of naturally-occuring mutations (3); if dominant negative inhibition is also central to the 132 pathogenesis of RTH, this property may also constrain localisation of RTHmutations within TR. 133 Seven out of fourteen TR mutations recorded hitherto have occurred de novo, with mutations 134 involving some residues (e.g. Alanine 263, Arginine 384, Glutamic Acid 403) occurring more than 5 135 once in unrelated families; as has been shown in RTH (21), it is possible that nucleotide substitutions 136 involving mutation-prone, CpG dinucleotides will occur more frequently, resulting in some aminoacid 137 changes being overrepresented. 138 Although not identified via neonatal screening (in a program with both T4 and TSH measurement), 139 thyroxine therapy from age 18 months has been beneficial for growth, motor development and 140 constipation in a childhood case with a partial loss-of-function mutation (D211G) (13). Despite the 141 first recorded patient harbouring a more deleterious E403X TR mutation (5), we have observed 142 similar benefit following five years of thyroxine therapy (Moran, Chatterjee and Dattani unpublished 143 observations). Accordingly, despite the relative paucity of data, a trial of thyroxine therapy in RTH 144 cases harbouring both mild and severe loss-of-function TR mutations may be indicated. However, 145 careful surveillance to not only assess therapeutic benefit but also monitor for unwanted tissue toxicity 146 (e.g in liver, which expresses mainly TR), is warranted. In this context, as in RTH, reliable 147 biomarkers of tissue responses to TH are needed. In the future, it also conceivable that genetic 148 stratification may guide therapy of RTH patients, with thyroxine or selective thyromimetics being 149 used in patients harbouring TR mutations with residual functional activity, with alternative 150 approaches (e.g. blocking formation or activity of receptor-transcriptional corepressor complexes) in 151 cases with severe, hormone-refractory, TR defects. 152 153 ACKNOWLEDGEMENTS 154 155 We thank Dr Louise Fairall, Department of Molecular and Cell Biology, University of Leicester, UK 156 for the crystallographic modelling shown in Figure 2. 157 6 158 159 REFERENCES 160 161 1) Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993; 162 14:184-193. 163 164 2) Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 165 1993; 14:348-399. 166 167 3) Gurnell M, Visser T, Beck-Peccoz P and Chatterjee K. Resistance to thyroid hormone. 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Identical mutations in unrelated families with generalized 248 resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor β 249 gene. J Clin Invest 1993; 91:2408–2415. 250 10 251 FIGURE LEGENDS 252 Figure 1. 253 Schematic alignment of TR1, TR2 and TR showing functional regions (N-terminal, DNA 254 binding domain DBD, hormone binding domains); the divergent carboxyterminus of TRis cross- 255 hatched. The location of recorded RTH mutations, involving either TR1 alone or both TR1 and 256 2 proteins, is superimposed. Three regions of TR1 (aminoacids 234 to 282, 309 to 353 and 426 to 257 460), within which RTH mutations cluster are depicted. Within these clusters, published or our 258 unpublished (D265A) RTH mutations, involving aminoacids homologous to residues mutated in 259 RTH, are shown. 260 261 Figure 2: The crystal structure of the hormone binding domain of human TR1 bound to T3 (PDB 262 2H77, magenta) is shown. The location of aminoacids which are mutated (missense or premature stop 263 or frameshift/premature stop) in RTH is superimposed (red balls). The carboxyterminal region 264 (distal helix 11 to helix 12) within which RTH mutations occur, is highlighted in yellow. 265 11