The Experts below are selected from a list of 84 Experts worldwide ranked by ideXlab platform
Mehul T Dattani - One of the best experts on this subject based on the ideXlab platform.
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Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism.
The Journal of clinical endocrinology and metabolism, 2011Co-Authors: Kyriaki S Alatzoglou, Daniel Kelberman, Christopher T Cowell, Rodger Palmer, Ivo J P Arnhold, Maria E Melo, Dirk Schnabel, Annette Grueters, Mehul T DattaniAbstract:Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable Septooptic Dysplasia were screened for variability of the PA tract. We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress β-catenin mediated transcription in vitro. This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation.
Daniel Kelberman - One of the best experts on this subject based on the ideXlab platform.
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Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism.
The Journal of clinical endocrinology and metabolism, 2011Co-Authors: Kyriaki S Alatzoglou, Daniel Kelberman, Christopher T Cowell, Rodger Palmer, Ivo J P Arnhold, Maria E Melo, Dirk Schnabel, Annette Grueters, Mehul T DattaniAbstract:Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable Septooptic Dysplasia were screened for variability of the PA tract. We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress β-catenin mediated transcription in vitro. This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation.
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HESX1 mutations are an uncommon cause of Septooptic Dysplasia and hypopituitarism
The Journal of clinical endocrinology and metabolism, 2006Co-Authors: David E. G. Mcnay, Kathryn S. Woods, Daniel Kelberman, James P. G. Turton, Raja Brauner, Anastasios Papadimitriou, Eberhard Keller, A. Keller, Nele Haufs, Heiko KrudeAbstract:Context: Mutations in the transcription factor HESX1 have previously been described in association with Septooptic Dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis. Objective: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an indepth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. Design: Nonfamilial patients (724) with either SOD (n 314) or isolatedpituitarydysfunction,opticnervehypoplasia,ormidlineneurological abnormalities (n 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. Patients: All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects). Results: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. Conclusions: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis. (J Clin Endocrinol Metab 92: 691–697, 2007)
Kyriaki S Alatzoglou - One of the best experts on this subject based on the ideXlab platform.
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Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism.
The Journal of clinical endocrinology and metabolism, 2011Co-Authors: Kyriaki S Alatzoglou, Daniel Kelberman, Christopher T Cowell, Rodger Palmer, Ivo J P Arnhold, Maria E Melo, Dirk Schnabel, Annette Grueters, Mehul T DattaniAbstract:Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable Septooptic Dysplasia were screened for variability of the PA tract. We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress β-catenin mediated transcription in vitro. This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation.
Sally Radovick - One of the best experts on this subject based on the ideXlab platform.
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Enhanced repression by HESX1 as a cause of hypopituitarism and Septooptic Dysplasia.
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Ronald N. Cohen, Laurie E. Cohen, Diego Botero, Angela Sagar, Magdalena Jurkiewicz, Sally RadovickAbstract:HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of Septooptic Dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.
Heiko Krude - One of the best experts on this subject based on the ideXlab platform.
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HESX1 mutations are an uncommon cause of Septooptic Dysplasia and hypopituitarism
The Journal of clinical endocrinology and metabolism, 2006Co-Authors: David E. G. Mcnay, Kathryn S. Woods, Daniel Kelberman, James P. G. Turton, Raja Brauner, Anastasios Papadimitriou, Eberhard Keller, A. Keller, Nele Haufs, Heiko KrudeAbstract:Context: Mutations in the transcription factor HESX1 have previously been described in association with Septooptic Dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis. Objective: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an indepth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. Design: Nonfamilial patients (724) with either SOD (n 314) or isolatedpituitarydysfunction,opticnervehypoplasia,ormidlineneurological abnormalities (n 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. Patients: All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects). Results: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. Conclusions: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis. (J Clin Endocrinol Metab 92: 691–697, 2007)
