Genetische fout veroorzaakt veel problemen met hypothyreoïdie

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Lid geworden op: 08 nov 2014, 17:53

Genetische fout veroorzaakt veel problemen met hypothyreoïdie

Bericht door ineke » 26 okt 2018, 13:10

Volledig artikel in Journal of Clinical Investigation

Nieuw onderzoek met senior auteur Antonio Bianco (hoogleraar geneeskunde Universiteit van Chicago)


Genetic flaw causes problems for many with hypothyroidism

With an estimated 120 million prescriptions filled each year, the thyroid medicine levothyroxine (marketed as Synthroid ) is one of the most popular prescription medicines in the United States.
Most patients who suffer from hypothyroidism—a shortage of thyroid hormone, usually caused by a damaged or missing thyroid gland—respond favorably to treatment with this drug.

Nearly 15 percent of patients, however, get only limited benefit from levothyroxine. Their symptoms, such as fatigue, weakness, weight gain, cramps, irritability and often memory loss, persist, even among patients who take this affordable medicine consistently.

On October 23, 2018 the Journal of Clinical Investigation posted an 'in-press preview" of this multi-institutional study, describing how one dysfunctional protein can disrupt the efficacy of this otherwise highly effective treatment.
The damage is caused by an inherited mutation in a critical enzyme that puts nearly one out of five patients at risk for not being able to experience the established benefits of levothyroxine.

"Even though they take their medications, many hypothyroid patients continue to have problems," said thyroid specialist Antonio Bianco, MD, Ph.D., professor of medicine at the University of Chicago and senior author of the study. "
They lack energy, they feel unfocused and they have trouble losing weight. They are properly taking thyroid hormone but their problems aren't going away. They get frustrated when they see little change, only limited improvement. Many change physicians multiple times, sometimes more than 10 times."

"In this study, using mice," he added, "we found compelling evidence that the explanation for this problem is a genetic polymorphism that significantly alters the crucial enzyme that metabolizes thyroid hormone. We are seeking ways to fix this."


How it doesn't work
The primary hormone secreted by the thyroid gland is thyroxine, also known as T4; levothyroxine is the pharmaceutical version of T4.
Soon after a patient takes the levothyroxine tablet, T4 is absorbed and enters the circulation, but to gain full biological activity, T4 must be converted to T3 (triiodothyronine).
This task is carried out by many cells, including the glial cells in the brain. The conversion relies on an enzyme known as type-2 deiodinase (D2).

Inside these cells, small membrane-wrapped vesicles shuttle D2 back and forth between two intracellular organelles, the endoplasmic reticulum (ER) and the Golgi apparatus.
In as many as 20 percent of people who rely on levothyroxine, however, the tiny genetic flaw in D2 causes the shuttling process to go astray. Those patients have a single-nucleotide substitution in the DNA that encodes D2. As a result, one amino acid, threonine, is replaced by a different amino acid, alanine.

This amino-acid switch, known as the Thr92Ala-DIO2 polymorphism, results in a misfolded D2 protein. Because cells recognize it as an abnormal protein, it gets pushed out of the ER and accumulates in distal portions of the Golgi apparatus.
Misfolded D2 is less active. It converts some T4 to T3, but the result is a significant overall decrease in the amount of available T3.

"Indeed, the brains of mice carriers of the polymorphism exhibit signs of hypothyroidism," said Bianco. The buildup of misfolded D2 in the ER and Golgi "disrupts the protein homeostasis of the cells, probably complicating things long term for patients who carry this polymorphism."
Patients with the polymorphism, for example, have been reported to be "at higher risk for problems including hypertension, insulin resistance, type 2 diabetes, and multiple cognitive issues.
A previous Bianco-led study, performed at Rush University Medical Center, found that African Americans carriers of this polymorphism have a 30 percent higher risk of developing Alzheimer's disease.


Going back to the mice
These findings led the team to create mice with the threonine-to-alanine polymorphism so they could probe its effects on the brain. "You can't easily study this in humans," Bianco explained, "so we turned to the brains of gene-altered mice."

They were surprised to see that test mice behave in many ways like humans with hypothyroidism. Their activities seemed to coincide with how patients feel. They sleep four times as much during day and night. They stay quiet, don't move around much. They lack the motivation to jump on the spinning wheel and play. They also exhibit memory problems.

A logical explanation is that these mice have brain hypothyroidism, despite having normal thyroid hormone levels in the blood. The researchers tested this theory by screening different parts of the brain for signs of hypothyroidism.
The brains of mice carriers of the D2 polymorphism clearly had areas with hypothyroid-like features, specifically in the striatum, pre-frontal cortex and amygdala, areas involved in motivation and decision-making processes.

To confirm this, they treated these animals with T3, and many of the aspects indicating hypothyroid-like behavior were normalized. Unfortunately, long-term treatment of patients with T3 has its drawbacks.
T3 has a short half-life. The tablets are rapidly absorbed, which causes levels to spike in the blood. Even at low doses, this can induce palpitations, anxiety, sweating and tightness of the chest.

"We do not know what damage these spikes can cause long-term," Bianco said. "Because people didn't appreciate that T3 was important for hypothyroid patients, the safety studies were never performed." He expects to open a clinical trial of a new agent in 2019.

"We hope that understanding these mechanisms will accelerate development of new therapeutic approaches for the millions of patients with hypothyroidism," the authors conclude, "and provide justification for clinical studies to assess the utility of customization of thyroid replacement therapy based on their Thr92Ala-DIO2 status."

Bron: med.express

Vertaald met google translate:
Genetische fout veroorzaakt veel problemen met hypothyreoïdie

Met naar schatting 120 miljoen recepten per jaar, is de levothyroxine voor de schildklier (op de markt gebracht als Synthroid) een van de meest populaire receptgeneesmiddelen in de Verenigde Staten.
De meeste patiënten met hypothyreoïdie - een tekort aan schildklierhormoon, meestal veroorzaakt door een beschadigde of ontbrekende schildklier - reageren gunstig op de behandeling met dit medicijn.

Bijna 15 procent van de patiënten krijgt echter slechts beperkt profijt van levothyroxine.
Hun symptomen, zoals vermoeidheid, zwakte, gewichtstoename, krampen, prikkelbaarheid en vaak geheugenverlies, blijven bestaan, zelfs bij patiënten die dit betaalbare medicijn consequent innemen.

Op 23 oktober 2018 publiceerde de Journal of Clinical Investigation een 'in-press preview' van deze multi-institutionele studie, waarin wordt beschreven hoe een niet-functioneel eiwit de werkzaamheid van deze anders zeer effectieve behandeling kan verstoren.
De schade wordt veroorzaakt door een overgeërfde mutatie in een kritisch enzym dat bijna een op de vijf patiënten in gevaar brengt omdat het niet in staat is om de gevestigde voordelen van levothyroxine te ervaren.

"Ook al nemen ze hun medicijnen in, veel hypothyreoïdiepatiënten blijven problemen hebben", zegt schildklierspecialist Antonio Bianco, MD, Ph.D., hoogleraar geneeskunde aan de Universiteit van Chicago en senior auteur van het onderzoek.
"Ze missen energie, ze voelen zich ongericht en hebben moeite om af te vallen, ze nemen goed schildklierhormoon, maar hun problemen gaan niet weg.
Ze raken gefrustreerd wanneer ze weinig verandering zien, slechts een beperkte verbetering. Veel veranderen artsen meerdere keren, soms meer dan 10 keer. "
"In deze studie, met behulp van muizen," vonden we, " overtuigend bewijs dat de verklaring voor dit probleem een genetisch polymorfisme is dat het cruciale enzym dat het schildklierhormoon metaboliseert aanzienlijk verandert."
We zijn op zoek naar manieren om dit te verhelpen. "


Hoe het werkt
Het primaire hormoon dat wordt uitgescheiden door de schildklier is thyroxine, ook bekend als T4; levothyroxine is de farmaceutische versie van T4.
Kort nadat een patiënt de levothyroxine-tablet heeft ingenomen, wordt T4 geabsorbeerd en komt het in de bloedsomloop, maar om volledige biologische activiteit te bereiken, moet T4 worden omgezet in T3 (trijoodthyronine).
Deze taak wordt uitgevoerd door vele cellen, inclusief de gliacellen in de hersenen.
De conversie berust op een enzym dat bekend staat als type-2 deiodinase (D2).

Binnenin deze cellen brengen kleine met membraan omwikkelde vesikels D2 heen en weer tussen twee intracellulaire organellen, het endoplasmatisch reticulum (ER) en het Golgi-apparaat.
Bij maar liefst 20 procent van de mensen die afhankelijk zijn van levothyroxine, veroorzaakt het kleine genetische defect in D2 echter dat het pendelproces verdwaalt.
Die patiënten hebben een single-nucleotide substitutie in het DNA dat codeert voor D2. Als een resultaat is één aminozuur, threonine, vervangen door een ander aminozuur, alanine.

Deze aminozuurschakelaar, bekend als het Thr92Ala-DIO2-polymorfisme, resulteert in een verkeerd gevouwen D2-eiwit.
Omdat cellen het herkennen als een abnormaal eiwit, wordt het uit de ER geduwd en hoopt het zich op in distale delen van het Golgi-apparaat.
Verkeerd gevouwen D2 is minder actief. Het converteert wat T4 naar T3, maar het resultaat is een significante algemene afname van de hoeveelheid beschikbare T3.

"Inderdaad, de hersenen van dragers van muizen van het polymorfisme vertonen tekenen van hypothyreoïdie," zei Bianco.
De opeenhoping van verkeerd gevouwen D2 in het ER en Golgi "verstoort de eiwithomeostase van de cellen, waarschijnlijk complicaties op de lange termijn voor patiënten die dit polymorfisme dragen."

Van patiënten met het polymorfisme is bijvoorbeeld gemeld dat ze "een hoger risico lopen op problemen zoals hypertensie, insulineresistentie, diabetes type 2 en meerdere cognitieve problemen."
Een eerder door Bianco geleid onderzoek, uitgevoerd in Rush University Medical Center, vond dat de dragers van Afrikaanse Amerikanen van dit polymorfisme hebben een 30 procent hoger risico om de ziekte van Alzheimer te ontwikkelen.


Terug naar de muizen
Deze bevindingen leidden ertoe dat het team muizen met het threonine-tot-alanine polymorfisme creëerde, zodat ze de effecten ervan op de hersenen konden onderzoeken.
"Je kunt dit niet gemakkelijk in mensen bestuderen," legde Bianco uit, "dus we keken naar de hersenen van gen-veranderde muizen."

Ze waren verrast om te zien dat testmuizen zich op veel manieren gedragen als mensen met hypothyreoïdie.
Hun activiteiten leken samen te vallen met hoe patiënten zich voelen. Ze slapen vier keer zoveel als dag en nacht. Ze blijven stil, bewegen niet veel. Ze missen de motivatie om op het draaiende wiel te springen en te spelen. Ze vertonen ook geheugenproblemen.

Een logische verklaring is dat deze muizen hypothyreoïdie in de hersenen hebben, ondanks het feit dat ze normale schildklierhormoonspiegels in het bloed hebben.
De onderzoekers testten deze theorie door verschillende delen van de hersenen te screenen op tekenen van hypothyreoïdie.
De hersenen van muizendragers van het D2-polymorfisme hadden duidelijk gebieden met hypothyreoïde-achtige kenmerken, met name in het striatum, de pre-frontale cortex en amygdala, gebieden die betrokken zijn bij motivatie en besluitvormingsprocessen.

Om dit te bevestigen, behandelden ze deze dieren met T3 en veel van de aspecten die op hypothyroid-achtig gedrag duidden, werden genormaliseerd.
Helaas heeft een langdurige behandeling van patiënten met T3 nadelen.

T3 heeft een korte halfwaardetijd. De tabletten worden snel geabsorbeerd, waardoor de spikkels in het bloed stijgen. Zelfs bij lage doses kan dit hartkloppingen, angstgevoelens, zweten en beklemming op de borst veroorzaken.
"We weten niet welke schade deze pieken op lange termijn kunnen veroorzaken," zei Bianco.
"Omdat mensen niet wisten dat T3 belangrijk was voor patiënten met hypothyreoïdie, werden de veiligheidsstudies nooit uitgevoerd."
Hij verwacht in 2019 een klinische proef met een nieuwe agent te openen.

"We hopen dat het begrijpen van deze mechanismen de ontwikkeling van nieuwe therapeutische benaderingen voor de miljoenen patiënten met hypothyreoïdie zal versnellen," concluderen de auteurs, "en bieden een rechtvaardiging voor klinische studies om het nut van maatwerk van schildkliervervangingstherapie te beoordelen op basis van hun Thr92Ala-DIO2 -status."


Abstract
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
Sungro Jo, … , Miriam O. Ribeiro, Antonio C. Bianco

Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism.
In the brain, T4 is converted to the active form T3 by the type 2 deiodinase (D2).
Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement
when liothyronine (LT3) is added to LT4 therapy.
Here we report that D2 is a cargo protein in endoplasmic reticulum Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi.
The Thr92 to Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR); Ala92-D2 accumulated in the trans-Golgi and generated less T3, all of which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA).
An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more and required additional time to memorize objects.
Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with
4-PBA eliminated the Ala92-Dio2 phenotype.
In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers
of Thr92Ala-DIO2.

Sungro Jo1,2, Tatiana L. Fonseca1,3, Barbara M. L. C. Bocco1,3, Gustavo W. Fernandes3, Elizabeth A. McAninch2, Anaysa P. Bolin2,4, Rodrigo R. Da Conceição2,5, Joao Pedro W. S. De Castro2, Daniele L. Ignacio2, Péter Egri6, Dorottya Németh6,Csaba Fekete6, Maria Martha Bernardi7, Victoria D. Leitch8, Naila S. Mannan8, Katharine F. Curry8, Natalie C. Butterfield8, J. H. Duncan Bassett8, Graham R. Williams8, Balázs Gereben6, Miriam O. Ribeiro9, Antonio C. Bianco3

2 Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL;
3 Section of Adult & Pediatric Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Chicago, Chicago IL
4 Department of Pharmacology, Biomedical Science Institute, University of São Paulo, São Paulo, SP, Brazil;
5 Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, SP, Brazil;
6 Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary;
7 Graduate Program of Environmental and Experimental Pathology, Graduate Program of Dentistry, Universidade Paulista, Sao Paulo, SP, Brazil;
8 Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK
9 Developmental Disorders Program, Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo, SP, Brazil
1 authors contributed equally to this work

Corresponding author:
Antonio C. Bianco, MD, PhD Section of Adult & Pediatric Endocrinology, Diabetes & Metabolism,
University of Chicago Medical Center
Conflict of interest statement: Dr. Bianco is a consultant for Sentier LLC and Synthonics Inc; the
other authors have declared that no conflict of interest exist.




Volledig artikel:
https://www.jci.org/articles/view/123176/pdf



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laura
Berichten: 2903
Lid geworden op: 11 sep 2013, 22:42
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Re: Genetische fout veroorzaakt veel problemen met hypothyreoïdie

Bericht door laura » 02 jan 2019, 14:13

Cognitive function in hypothyroidism: what is that deiodinase again?
Arturo Hernandez | Reference information: J Clin Invest. https://doi.org/10.1172/JCI125203.

Dit artikel geeft commentaar op bovengenoemd onderzoek.

Abstract

Treatment of hypothyroidism involves the endogenous conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) and may not be optimal in some cases when based on T4 alone. In the current issue of the JCI, Jo et al. present results that explain the reduced enzymatic activity of a common genetic variant of the enzyme responsible for this conversion, type 2 deiodinase (DIO2). The authors further explore the functional consequences of this variant on brain T3 activity, endoplasmic reticulum stress in glial cells, and cognitive function. These findings have important implications for the clinical treatment of hypothyroidism and for susceptibility to other neurological and metabolic diseases.

Role of DIO2 in thyroid hormone therapy

Whether due to autoimmune thyroid disease or secondary to the removal of the thyroid gland, hypothyroidism is a highly prevalent condition that affects 5% to 10% of the adult population (1). Thyroid hormone therapy, which is based on the administration of thyroxine (T4, 3,3′,5,5′-tetraiodothyronine), is used to help hypothyroid patients normalize their metabolism, cardiac function, mood, and cognition. However, to attain its full ability to regulate gene transcription in target cells, T4 must be converted to 3,5,3′-triiodothyronine (T3), the thyroid hormone that binds specific nuclear receptors with high affinity (2). This conversion process is largely accomplished by type 2 deiodinase (DIO2 or D2) (3).

Although this treatment is generally efficient, about 15% of patients are resistant and show persistent neurological symptoms, including deficits in memory and mood, even after T4 dosage is individually adjusted (4). Given the heavy reliance of this treatment on DIO2 function, investigators have explored DIO2 further and have been intrigued by the presence of a SNP in the human DIO2 gene (5). This SNP is present in up to a third of the human population and results in the change of a threonine (Thr) to an alanine (Ala) in amino acid 92 of the DIO2 polypeptide chain. The substitution affects a small and conserved domain of the protein involved in binding ubiquitin ligases (6), directing the enzyme for proteasomal degradation in a process that depends on the relative abundance and binding of its substrate, T4 (7).

Although initial assays on sonicates from transfected cells showed no deficits in the activity of Ala92-DIO2, studies in intact cells indicated reduced deiodination (8, 9), suggesting that the function of Ala-DIO2 is impaired in a physiological context. This notion was further supported by the clinical benefit that hypothyroid patients carrying this DIO2 SNP obtained from a combination therapy of T4 and T3 (10, 11).

Reduced functionality of Ala92-DIO2 explored

Why would Ala92-DIO2 not be fully functional in vivo? What would be the implications for brain thyroid hormone homeostasis and neurological function? In a remarkable bedside-to-bench work published in this issue of the JCI, Sungro Jo and Tatiana Fonseca, together with colleagues from a multiinstitutional team lead by Antonio Bianco, provide some critical answers to those questions and expand on the clinical implications of the Thr92Ala-DIO2 SNP (12).

In addition to confirming that intact transgenic cells expressing Ala-DIO2 exhibit a reduction in T3 production from T4, the authors observed that DIO2 is recycled between the ER and the Golgi using ER Golgi intermediary compartment (ERGIC) vesicles. They further showed (Figure 1) that the presence of this SNP causes ER stress and impairs ERGIC-mediated shuttling of Ala92-DIO2, which is then abnormally accumulated in the central Golgi, where it is enzymatically inactive.

Pathological basis of Ala92-DIO2. Thr92-DIO2 localizes in the ER where, with the support of appropriate cofactors, it is able to convert T4 into T3 for transcriptional regulation in the nucleus. DIO2 is recycled through the Golgi. Ala92-DIO2 causes ER stress and impairs the recycling of DIO2, which aberrantly accumulates in the Golgi, where it is not active. ER stress and decreased T3 production exert biological effects on glial cells and neurons, affecting neurological function.

If Ala92-DIO2 enzymatic activity is impaired in vivo, what are the functional consequences for the brain, a tissue highly dependent on T3 generated locally by DIO2 (13)? DIO2 is present in glial cells, where it also provides T3 for biological activity in neurons (14). This critical role has been further underscored by the abnormalities in behavior and brain gene expression observed in mice with astrocyte-specific DIO2 deficiency (15). Using “humanized” transgenic mice, Jo et al. showed that the subcellular abnormalities of Ala92-DIO2 were associated with decreased T3 action in the brain. Mice expressing the Ala92-DIO2 variant are euthyroid, based on serum parameters. However, areas of their brains exhibited decreased T3-dependent gene expression and abnormalities in the expression of genes related to ER stress and the ERGIC system. Furthermore, these mice exhibited impaired short-term memory, reduced levels of spontaneous physical activity, and increased sleep, characteristics that resemble those of clinical hypothyroidism.

The gene expression changes in the Ala92-DIO2 brains may seem too modest to cause a neurological phenotype. However, the brain is notorious for its strict and spatial-specific regulation of thyroid hormone levels. In fact, when Ala92-DIO2 mice were treated with T3, their levels of physical activity were normalized, demonstrating that at least some of their neurological deficits were actually caused by local T3 deficiency. Furthermore, the authors examined neurological function after rendering the mice hypothyroid with antithyroid drugs, a model that recapitulates the clinical condition of many hypothyroid patients and eliminates the biological contribution of the T3 secreted by the thyroid gland. When hypothyroid, both Thr92-DIO2 and Ala92-DIO2 mice showed neurological deficits affecting memory, sleep, and locomotor activity. However, after T4 administration, this phenotype was rescued only in Thr92-DIO2 mice and not in Ala92-DIO2 mice. In the latter, neurological function was normalized only when the mice were treated with a combination of T4 and T3. These findings again highlight the deficit in brain T3 associated with Ala92-DIO2, a situation that could become even more critical in the context of hypothyroidism secondary to thyroid disease, as seen in human patients.

Broader implications of the study

There are additional and highly intriguing aspects of this work. As mentioned above, in intact Ala92-DIO2 mice, T3 treatment rescues only one of the neurological phenotypes examined. However, normalizing protein homeostasis with an ER stress inhibitor fully restores the neurological functions. This observation suggests that, at least under serum euthyroid conditions, part of the neurological pathophysiology of Ala92-DIO2 mice is primarily due to of ER stress. In this scenario, ER stress can potentially lead, not only to mislocalization of DIO2 and reduced T3 generation, but also to glial cell dysfunction, potentially influencing neuronal physiology. This possibility is consistent with epidemiological studies showing increased prevalence of bipolar disorder and Alzheimer’s disease in individuals carrying the Ala92-DIO2 polymorphism (16). It would be interesting to determine whether Ala92-DIO2 contributes to age-related cognitive decline and neurodegeneration, especially in the context of the natural changes in thyroid function associated with age.

It is also conceivable that other neurological abnormalities of Ala92- DIO2 mice not identified in this work could partly originate during development, either as a consequence of ER stress alone or combined with reduced local T3 generation. DIO2 expression in most rodent brain regions peaks during neonatal stages, when T3 action and responsiveness are highest in the central nervous system (17). It is then possible that impaired T3 generation in Ala92-DIO2 carriers may influence brain development and explain the increased incidence of mental retardation associated with this DIO2 variant (16).

The extent to which hypothyroid patients with T4-resistant neurological symptoms coincide with those carrying Ala92-DIO2 is not yet clear. Even if this is only partially the case, the presence of Ala92-DIO2 appears as an important risk factor for suboptimal treatment of hypothyroidism, and the present work is a substantial advance in understanding the cellular and molecular basis of this risk.

Clinical implications of Ala92-DIO2 SNP pathology

The high prevalence of hypothyroidism, the relatively high abundance of the Ala92-DIO2 variant in the human population, and the presence of DIO2 in many areas of the central nervous system and other tissues confer broad clinical relevance to the present work and strongly warrant additional studies. Work examining the interacting proteins responsible for the altered subcellular homeostasis of Ala92-DIO2 and defining the thyroid status in which these interactions are most critical to pathophysiology could yield important mechanistic insights. Research defining the pathological contributions of ER stress and T3 deficiency or focusing on specific brain regions and additional neurological functions is also warranted. Finally, given the associations of this SNP with increased metabolic abnormalities, it is also possible that disease susceptibility in Ala92-DIO2 carriers is partly the result of thyroid hormone alterations in nonneural, DIO2-expressing tissues. Our understanding of the pathological basis of the Ala92-DIO2 SNP has just begun, and clinical implications may extend well beyond the treatment of hypothyroidism.

Reference information: J Clin Invest. https://doi.org/10.1172/JCI125203.
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