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Peter Kopp - One of the best experts on this subject based on the ideXlab platform.
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2, 3), only 3 years after the cloning of the THR genes (4, 5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8, 9) and a defect reducing the intraCellular metabolism generating T3 from T4 (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11, 12), we propose using the term “RTH α”, and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20 000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
European thyroid journal, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 [1], and the first mutations in the THRB gene were identified in 1989 [2,3], only 3 years after the cloning of the THR genes [4,5]. The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis [6]. In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH [7], as defined above. In the ensuing years more than 3,000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport [8,9] and a defect reducing the intraCellular metabolism generating T3 from T4[10]. To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term ‘reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts'. Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (table (table1).1). The term ‘impaired’ was to substitute for ‘reduced’ because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications ‘RTH’ is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype [11,12], we propose using the term ‘RTH α’, and in new publications to use ‘RTH β’ when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation ‘THR’ as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1 Inheritable forms of impaired sensitivity to thyroid hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
Thyroid, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2,3), only three years after the cloning of the THR genes (4,5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed thyrotropin (TSH), often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom, in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, triiodothyronine (T3), were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8,9) and a defect reducing the intraCellular metabolism generating T3 from thyroxine (T4) (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11,12), we propose using the term “RTH α,” and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
Juan Bernal - One of the best experts on this subject based on the ideXlab platform.
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2, 3), only 3 years after the cloning of the THR genes (4, 5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8, 9) and a defect reducing the intraCellular metabolism generating T3 from T4 (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11, 12), we propose using the term “RTH α”, and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20 000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
European thyroid journal, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 [1], and the first mutations in the THRB gene were identified in 1989 [2,3], only 3 years after the cloning of the THR genes [4,5]. The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis [6]. In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH [7], as defined above. In the ensuing years more than 3,000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport [8,9] and a defect reducing the intraCellular metabolism generating T3 from T4[10]. To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term ‘reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts'. Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (table (table1).1). The term ‘impaired’ was to substitute for ‘reduced’ because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications ‘RTH’ is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype [11,12], we propose using the term ‘RTH α’, and in new publications to use ‘RTH β’ when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation ‘THR’ as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1 Inheritable forms of impaired sensitivity to thyroid hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
Thyroid, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2,3), only three years after the cloning of the THR genes (4,5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed thyrotropin (TSH), often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom, in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, triiodothyronine (T3), were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8,9) and a defect reducing the intraCellular metabolism generating T3 from thyroxine (T4) (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11,12), we propose using the term “RTH α,” and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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thyroid hormone Transport in developing brain
Current Opinion in Endocrinology Diabetes and Obesity, 2011Co-Authors: Juan BernalAbstract:PURPOSE OF REVIEW To discuss the recent advances on thyroid hormone Transport in the brain. A special attention is paid to the X-linked thyroid hormone Cell Transport (THCT) defect (also known as the Allan-Herndon-Dudley syndrome), caused by mutations of the specific thyroid hormone Transporter MCT8 gene. RECENT FINDINGS MCT8 is involved in thyroid hormone Transport in the brain. MRI of patients with THCT defect showed myelination delays, probably related to impaired thyroid hormone action on oligodendrocytes. MCT8 is also expressed in the thyroid and has an important role in thyroid hormone secretion. The altered circulating concentrations of thyroid hormone in the patients are partly because of impaired secretion and altered peripheral metabolism. Increased deiodinase activity is important in the pathophysiology of the syndrome. High D1 activity in liver and kidney increases T4 and rT3 deiodination, and contributes to the increased serum T3. High D2 activity in the brain contributes to compensate the deficient T3 Transport by increasing local T3 production. SUMMARY Patients with suspected X-linked leukoencephalopathy should be screened for MCT8 gene mutations. Research on the brain pathophysiology of the THCT defect should focus on the specific role of Mct8 on oligodendrocytes and myelination.
Manfred Heinlein - One of the best experts on this subject based on the ideXlab platform.
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comparison of the oilseed rape mosaic virus and tobacco mosaic virus movement proteins mp reveals common and dissimilar mp functions for tobamovirus spread
Virology, 2014Co-Authors: Annette Niehl, Adrien Pasquier, Inmaculada Ferriol, Yves Mely, Manfred HeinleinAbstract:Tobacco mosaic virus (TMV) is a longstanding model for studying virus movement and macromolecular Transport through plasmodesmata (PD). Its movement protein (MP) interacts with cortical microtubule (MT)-associated ER sites (C-MERs) to facilitate the formation and Transport of ER-associated viral replication complexes (VRCs) along the ER-actin network towards PD. To investigate whether this movement mechanism might be conserved between tobamoviruses, we compared the functions of Oilseed rape mosaic virus (ORMV) MP with those of MPTMV. We show that MPORMV supports TMV movement more efficiently than MPTMV. Moreover, MPORMV localizes to C-MERs like MPTMV but accumulates to lower levels and does not localize to larger inclusions/VRCs or along MTs, patterns regularly seen for MPTMV. Our findings extend the role of C-MERs in viral Cell-to-Cell Transport to a virus commonly used for functional genomics in Arabidopsis. Moreover, accumulation of tobamoviral MP in inclusions or along MTs is not required for virus movement. (C) 2014 Elsevier Inc. All rights reserved.
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2, 3), only 3 years after the cloning of the THR genes (4, 5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8, 9) and a defect reducing the intraCellular metabolism generating T3 from T4 (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11, 12), we propose using the term “RTH α”, and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20 000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
European thyroid journal, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 [1], and the first mutations in the THRB gene were identified in 1989 [2,3], only 3 years after the cloning of the THR genes [4,5]. The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis [6]. In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH [7], as defined above. In the ensuing years more than 3,000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone Cell membrane Transport [8,9] and a defect reducing the intraCellular metabolism generating T3 from T4[10]. To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term ‘reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts'. Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (table (table1).1). The term ‘impaired’ was to substitute for ‘reduced’ because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications ‘RTH’ is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype [11,12], we propose using the term ‘RTH α’, and in new publications to use ‘RTH β’ when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation ‘THR’ as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1 Inheritable forms of impaired sensitivity to thyroid hormone
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classification and proposed nomenclature for inherited defects of thyroid hormone action Cell Transport and metabolism
Thyroid, 2014Co-Authors: Samuel Refetoff, Juan Bernal, J Duncan H Bassett, Paolo Beckpeccoz, Gregory A Brent, Krishna Chatterjee, Leslie J De Groot, Alexandra M Dumitrescu, Larry J Jameson, Peter KoppAbstract:Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2,3), only three years after the cloning of the THR genes (4,5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed thyrotropin (TSH), often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom, in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced Cellular access of the biologically active thyroid hormone, triiodothyronine (T3), were identified. These are caused by defects of thyroid hormone Cell membrane Transport (8,9) and a defect reducing the intraCellular metabolism generating T3 from thyroxine (T4) (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11,12), we propose using the term “RTH α,” and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
Patricia Zambryski - One of the best experts on this subject based on the ideXlab platform.
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plant Cell Cell Transport via plasmodesmata is regulated by light and the circadian clock
Plant Physiology, 2019Co-Authors: Jacob O Brunkard, Patricia ZambryskiAbstract:Plasmodesmata (PD) are essential for plant development, but little is known about their regulation. Several studies have linked PD Transport to chloroplast-centered signaling networks, but the physiological significance of this connection remains unclear. Here, we show that PD Transport is strongly regulated by light and the circadian clock. Light promotes PD Transport during the day, but light is not sufficient to increase rates of PD Transport at night, suggesting a circadian gating mechanism. Silencing expression of the core circadian clock gene, LHY/CCA1, allows light to strongly promote PD Transport during subjective night, confirming that the canonical plant circadian clock controls the PD Transport light response. We conclude that PD Transport is dynamically regulated during the day/night cycle. Due to the many roles of PD in plant biology, this discovery has strong implications for plant development, physiology, and pathogenesis.
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plasmodesmata formation and Cell to Cell Transport are reduced in decreased size exclusion limit 1 during embryogenesis in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Euna Cho, Tessa M Burchsmith, Patricia ZambryskiAbstract:In plants, plasmodesmata (PD) serve as channels for micromolecular and macromolecular Cell-to-Cell Transport. Based on structure, PD in immature tissues are classified into two types, simple and branched (X- and Y-shaped) or twinned. The maximum size of molecules capable of PD Transport defines PD aperture, known as the PD size exclusion limit. Here we report an Arabidopsis mutation, decreased size exclusion limit1 (dse1), that exhibits reduced Cell-to-Cell Transport of the small (524 Da) fluorescent tracer 8-hydroxypyrene-1,3,6-trisulfonic acid at the midtorpedo stage of embryogenesis. Correspondingly, the fraction of X- and Y-shaped and twinned PD was reduced in dse1 embryos compared with WT embryos at this stage, suggesting that the frequency of PD is related to Transport capability. dse1 is caused by a point mutation in At4g29860 (previously termed TANMEI) at the last donor splice site of its transcript, resulting in alternative splicing in both the first intron and the last intron. AtDSE1 is a conserved eukaryotic 386-aa WD-repeat protein critical for Arabidopsis morphogenesis and reproduction. Similar to its homologs in mouse, null mutants are embryo-lethal. The weak loss-of-function mutant dse1 exhibits pleiotropic phenotypes, including retarded vegetative growth, delayed flowering time, dysfunctional male and female organs, and delayed senescence. Finally, silencing of DSE1 in Nicotiana benthamiana leaves leads to reduced movement of GFP fused to tobacco mosaic virus movement protein. Thus, DSE1 is important for regulating PD Transport between plant Cells.
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loss of the plant dead box protein ise1 leads to defective mitochondria and increased Cell to Cell Transport via plasmodesmata
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Solomon Stonebloom, Tessa M Burchsmith, Insoon Kim, David W Meinke, Michael N Mindrinos, Patricia ZambryskiAbstract:Plants have interCellular channels, plasmodesmata (PD), that span the Cell wall to enable Cell-to-Cell Transport of micro- and macromolecules. We identified an Arabidopsis thaliana embryo lethal mutant increased size exclusion limit 1 (ise1) that results in increased PD-mediated Transport of fluorescent tracers. The ise1 mutants have a higher frequency of branched and twinned PD than wild-type embryos. Silencing of ISE1 in mature Nicotiana benthamiana leaves also leads to increased PD Transport, as monitored by interCellular movement of a GFP fusion to the tobacco mosaic virus movement protein. ISE1 encodes a putative plant-specific DEAD-box RNA helicase that localizes specifically to mitochondria. The N-terminal 100 aa of ISE1 specify mitochondrial targeting. Mitochondrial metabolism is compromised severely in ise1 mutant embryos, because their mitochondrial proton gradient is disrupted and reactive oxygen species production is increased. Although mitochondria are essential for numerous Cell-autonomous functions, the present studies demonstrate that mitochondrial function also regulates the critical Cell non-Cell-autonomous function of PD.
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Cell to Cell Transport of proteins and fluorescent tracers via plasmodesmata during plant development
Journal of Cell Biology, 2004Co-Authors: Patricia ZambryskiAbstract:Plant Cells communicate with each other via channels called plasmodesmata (PD). PD are not passive channels, but critical players in gene regulation, controlling interCellular Transport of macromolecules between particular Cells during development.