A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child
Autor(a) principal: | |
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Data de Publicação: | 2001 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1210/jcem.86.8.7765 http://hdl.handle.net/11449/224201 |
Resumo: | Congenital hypothyroidism associated with thyroid hypoplasia can be caused by several genetic defects, including mutations in the TSHβ-subunit, the TSH receptor, the Gsα-subunit, and the transcription factor PAX8. Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15). Mutations in the coding region of the TSHβ-subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsα had been excluded previously. Serum TSH concentrations were 150 mU/liter or more, TG levels were within normal limits, and thyroid auto-antibodies were absent. Technetium scintigraphies did not reveal the presence of thyroid tissue, but ultrasonography documented hypoplastic, normally located glands. One patient was found to harbor a heterozygous transversion 119A→C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P). Analysis of her family members revealed that her mother, who has a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, is also heterozygous for this mutation. Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent transactivation of a thyroid peroxidase promoter luciferase reporter gene. These findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity. The absence of mutations in the coding sequences of the analyzed genes in the three other patients supports the concept that the pathogenesis of congenital hypothyroidism associated with thyroid hypoplasia is diverse. |
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spelling |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and childCongenital hypothyroidism associated with thyroid hypoplasia can be caused by several genetic defects, including mutations in the TSHβ-subunit, the TSH receptor, the Gsα-subunit, and the transcription factor PAX8. Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15). Mutations in the coding region of the TSHβ-subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsα had been excluded previously. Serum TSH concentrations were 150 mU/liter or more, TG levels were within normal limits, and thyroid auto-antibodies were absent. Technetium scintigraphies did not reveal the presence of thyroid tissue, but ultrasonography documented hypoplastic, normally located glands. One patient was found to harbor a heterozygous transversion 119A→C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P). Analysis of her family members revealed that her mother, who has a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, is also heterozygous for this mutation. Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent transactivation of a thyroid peroxidase promoter luciferase reporter gene. These findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity. The absence of mutations in the coding sequences of the analyzed genes in the three other patients supports the concept that the pathogenesis of congenital hypothyroidism associated with thyroid hypoplasia is diverse.Division of Endocrinology Metabolism and Molecular Medicine Northwestern University, Chicago, IL 60611Pediatric Endocrinology Northwestern University, Chicago, IL 60611Laboratorio Molecular de Tiroide (LIM-25) Hospital das Clinicas Universidade de São Paulo, Sao PauloDepartamento de Clinica Médica Disciplina de Endocrinologia Faculdade de Medicina UNESP, BotucatuDivision of Endocrinology Metabolism and Molecular Medicine Northwestern University, Tarry 15, 303 East Chicago Avenue, Chicago, IL 60611Departamento de Clinica Médica Disciplina de Endocrinologia Faculdade de Medicina UNESP, BotucatuNorthwestern UniversityUniversidade de São Paulo (USP)Universidade Estadual Paulista (UNESP)Congdon, TamaraNguyen, Lynda Q.Nogueira, Celia R. [UNESP]Habiby, Reema L.Medeiros-Neto, GeraldoKopp, Peter2022-04-28T19:55:16Z2022-04-28T19:55:16Z2001-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article3962-3967http://dx.doi.org/10.1210/jcem.86.8.7765Journal of Clinical Endocrinology and Metabolism, v. 86, n. 8, p. 3962-3967, 2001.0021-972Xhttp://hdl.handle.net/11449/22420110.1210/jcem.86.8.77652-s2.0-0034885770Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Clinical Endocrinology and Metabolisminfo:eu-repo/semantics/openAccess2022-04-28T19:55:17Zoai:repositorio.unesp.br:11449/224201Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462022-04-28T19:55:17Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
title |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
spellingShingle |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child Congdon, Tamara |
title_short |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
title_full |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
title_fullStr |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
title_full_unstemmed |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
title_sort |
A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: Evidence for phenotypic variability in mother and child |
author |
Congdon, Tamara |
author_facet |
Congdon, Tamara Nguyen, Lynda Q. Nogueira, Celia R. [UNESP] Habiby, Reema L. Medeiros-Neto, Geraldo Kopp, Peter |
author_role |
author |
author2 |
Nguyen, Lynda Q. Nogueira, Celia R. [UNESP] Habiby, Reema L. Medeiros-Neto, Geraldo Kopp, Peter |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Northwestern University Universidade de São Paulo (USP) Universidade Estadual Paulista (UNESP) |
dc.contributor.author.fl_str_mv |
Congdon, Tamara Nguyen, Lynda Q. Nogueira, Celia R. [UNESP] Habiby, Reema L. Medeiros-Neto, Geraldo Kopp, Peter |
description |
Congenital hypothyroidism associated with thyroid hypoplasia can be caused by several genetic defects, including mutations in the TSHβ-subunit, the TSH receptor, the Gsα-subunit, and the transcription factor PAX8. Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15). Mutations in the coding region of the TSHβ-subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsα had been excluded previously. Serum TSH concentrations were 150 mU/liter or more, TG levels were within normal limits, and thyroid auto-antibodies were absent. Technetium scintigraphies did not reveal the presence of thyroid tissue, but ultrasonography documented hypoplastic, normally located glands. One patient was found to harbor a heterozygous transversion 119A→C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P). Analysis of her family members revealed that her mother, who has a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, is also heterozygous for this mutation. Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent transactivation of a thyroid peroxidase promoter luciferase reporter gene. These findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity. The absence of mutations in the coding sequences of the analyzed genes in the three other patients supports the concept that the pathogenesis of congenital hypothyroidism associated with thyroid hypoplasia is diverse. |
publishDate |
2001 |
dc.date.none.fl_str_mv |
2001-01-01 2022-04-28T19:55:16Z 2022-04-28T19:55:16Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1210/jcem.86.8.7765 Journal of Clinical Endocrinology and Metabolism, v. 86, n. 8, p. 3962-3967, 2001. 0021-972X http://hdl.handle.net/11449/224201 10.1210/jcem.86.8.7765 2-s2.0-0034885770 |
url |
http://dx.doi.org/10.1210/jcem.86.8.7765 http://hdl.handle.net/11449/224201 |
identifier_str_mv |
Journal of Clinical Endocrinology and Metabolism, v. 86, n. 8, p. 3962-3967, 2001. 0021-972X 10.1210/jcem.86.8.7765 2-s2.0-0034885770 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Clinical Endocrinology and Metabolism |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
3962-3967 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1799964819262013440 |