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THRA MUTATIONS CAUSING TH INSENSITIVITY

The question of why mutations in the THRA gene have not been identified earlier in man was partially answered by the study of mice with targeted gene manipulations. TRα gene deletions, total or only α1 and mice harboring mutation in the Thra gene, modeled after those in the Thrb gene, failed to produce serum thyroid tests abnormalities. Further, there was no evidence for central hypothyroidism and perturbations in metabolic regulations (157);. The first individual found to harbor a THRA gene defect was identified in 2012 by Bochukova et al. in a 6 year old girl by whole-exome sequencing (16).

Incidence, Prevalence

As of this writing, 13 subjects belonging to 9 families have been identified with THRA gene mutations (16,158-162) (Table 5). The proposita of the first case was, a white female of European descent. She was heterozygous for a de novo mutation in the THRA gene. A second family, of Greek ancestry, had an affected father and daughter. A fourth case was diagnosed at age 42 years in a woman with epilepsy, growth retardation, constipation and macrocephaly. Six additional families with THRA gene mutations were recently presented. The prevalence remains unknown (16,158-162).

Table 5. THRA gene mutations in humans

THRA gene Nucleotide #	THRA protein	FT4 % lower limit of normal	FT3 % upper limit of normal	TrT3 % lower limit of normal	TSH mU/L	Known THRB gene mutations in correspond-ding codons	Refeterence
806 C>T	A263V	99*	90*	<63*	4.2*	A317V/T/S/D	(161)
1075 A>T	N359Y	114	100	121	0.3		(160)
1144 delG	A382fsM388X	100	140	91	5.8	A436T/fs M442V/T	(159)
1176 C>A	C392X	107	148		2.8	C446X/G/R	(162)
1193 C>G	P398R	72	70		0.5	P452H/L/	(162)
1207 G>T	E403X	63	80		1.0	E457G	(16)
1207 G>T	E403X	NA	NA		NA	E457G	(162)
1207 G>A	E403K	106	90	33	1.9	E457G	(162)
1190 insT	F397fs E406X	Low Nl	High Nl	l	Nl	E460K	(158)

del, deletion; ins, insertion; Nl, normal; NA, data not available prior to treatment with L-T4.

* average for 3 affected adult members of the family.

The alternative splicing giving rise to TRa2 isoforms occurs at amino acid 372.

Clinical Features

In general RTH presents with a range of features that are characterized by growth retardation with skeletal dysplasia resulting in short lower limbs and large head, mental retardation constipation, bradycardia and reduced muscle strength. Other associated problems are seizures and red cell macrocytosis. These clinical findings are compatible with the known tissue distribution of the TR α in bone, brain, intestine, heart and muscle.

Laboratory Findings And Differential Diagnosis

Thyroid function tests in RTH have consistently demonstrated markedly low serum rT₃, slightly low or low normal T₄, relatively high normal T₃ and normal TSH. This constellation of thyroid tests is not explained by a defective feedback regulation at the hypothalamus and pituitary level, as these are mainly the functions of RTH. It has been demonstrated that TH regulation of deiodinase 3 (DIO3) is dependent on TR (163). Therefore, subjects with RTH may have a reduced DIO3 resulting in a low rT₃. The differential diagnosis would include TH cell transport defects, such as MCT8 deficiency, although the lack of severe psychomotor retardation in RTH and the lack of bone and growth defects in the MCT8 deficient patients are distinguishing features.

Genetic Pathophysiology

The inheritance is autosomal dominant. As is the case of TRß defects, the mutant TRα exerts dominant negative effect on the wild-type TR1 that binds T₃. The first three families reported had mutations that truncated the TR; these were M338X, E403X and E406X. Functionally, they corresponded to the following mutations in the TRß molecule: M442X, E457X and E460X, one of which, C446X has been reported (see table 5). The latter produce a very severe form of RTHß phenotype (164). More recently missense mutation that involve both the TR1 and TR2 isoforms have been reported, A263V and N359Y (160,161). The mutation affecting the TR2 isoform does not seam to contribute to the phenotype (161). While A382PfsX7 and N359Y both have dominant negative effects on TR1 and TR2, the A382PfsX7 mutant retains constitutive corepressor binding and there is an absence of coactivator recruitment. The reason for the unusual manifestations and somatic defects present in the subject with the THRA N359Y (160) remain unexplained.

Treatment

Given the limited experience with RTHα, there is no established therapy. Affected subjects have received trials of L-T₄ therapy that alleviated the constipation. Unless treatment is instituted in early life, it is unclear whether there will be improvement on mental function.