Reduced L- and M- and increased S-cone functions in an infant with thyroid hormone resistance due to mutations in the<i>THRβ2</i>gene

Weiss, Avery H.; Kelly, John P.; Bisset, Darren; Deeb, Samir S.

doi:10.3109/13816810.2012.681096

Cited by 46 publications

(29 citation statements)

References 60 publications

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“…This is in agreement with the observations in a human patient carrying TRβ2 mutations. This patient merely showed red/green color complications but rod morphology and rhodopsin expression level remained normal (32). In this study, we found no negative effect of antithyroid treatment on rod survival in our degenerating mouse models.…”

Section: Discussionmentioning

confidence: 46%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunitdeficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotidegated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.R od and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph. uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransductionassociated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotidegated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7,8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long ...

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Section: Discussionmentioning

confidence: 46%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Also, albeit rare, male patients are color blind in TH resistance syndrome, which represents a model for fetal hypothyroidism. In a case report, reduced L-and M-and increased S-cone functions in an infant with TH resistance due to mutations in the THRβ2 gene were demonstrated [21] . However, neither fetal hypothyroidism nor preterm infant studies may serve as appropriate models for adult hypothyroidism.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Hypothyroidism on Color Contrast Sensitivity: A Prospective Study

et al. 2015

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“…However, few studies in mice have successfully addressed the implications of these mutations in humans. 83 …”

Section: Thyroid Hormone Receptorsmentioning

confidence: 99%

Thyroid hormone receptors and resistance to thyroid hormone disorders

2014

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Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic–pituitary–thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

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Reduced L- and M- and increased S-cone functions in an infant with thyroid hormone resistance due to mutations in theTHRβ2gene

Cited by 46 publications

References 60 publications

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

The Effect of Hypothyroidism on Color Contrast Sensitivity: A Prospective Study

Thyroid hormone receptors and resistance to thyroid hormone disorders

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