title: A mouse model demonstrates a multigenic origin of congenital hypothyroidism.
abstract: Congenital hypothyroidism with thyroid dysgenesis (TD) is a frequent human condition characterized by elevated levels of TSH in response to reduced thyroid hormone levels. Congenital hypothyroidism is a genetically heterogeneous disease. In the majority of cases studied, no causative mutations have been identified and very often the disease does not show a Mendelian transmission. However, in approximately 5% of cases, it can be a consequence of mutations in genes encoding the TSH receptor or the transcription factors TITF1, FOXE1, or PAX8. We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice. The disease is characterized by a small thyroid gland, elevated levels of TSH, reduced thyroglobulin biosynthesis, and high occurrence of hemiagenesis. The observed phenotype is strain specific, and the pattern of transmission indicates that at least two other genes, in addition to Titf1 and Pax8, are necessary to generate the condition. These results show that TD can be of multigenic origin in mice and strongly suggest that a similar pathogenic mechanism may be observed in humans.
authors.affiliation: Stazione Zoologica A. Dohrn, Laboratorio di Genetica Animale at CEINGE, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Amendola
authors.forename: Pasquale
authors.initials: P
authors.lastname: De Luca
authors.forename: Paolo Emidio
authors.initials: PE
authors.lastname: Macchia
authors.forename: Daniela
authors.initials: D
authors.lastname: Terracciano
authors.forename: Annamaria
authors.initials: A
authors.lastname: Rosica
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
authors.forename: Andrea
authors.initials: A
authors.lastname: Affuso
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Macchia
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Lauro
authors.forename: Mario
authors.initials: M
authors.lastname: De Felice
mesh_terms: D000818:Animals; D020090:Chromosome Segregation; D003409:Congenital Hypothyroidism / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005808:Genes, Recessive; D006579:Heterozygote; D007037:Hypothyroidism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D013954:Thyroglobulin / Q000096:biosynthesis; D050033:Thyroid Dysgenesis / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D013972:Thyrotropin / Q000097:blood; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D013972:Thyrotropin; D013954:Thyroglobulin