A mouse model demonstrates a multigenic origin of congenital hypothyroidism

被引:96
作者
Amendola, E
De Luca, P
Macchia, PE
Terracciano, D
Rosica, A
Chiappetta, G
Kimura, S
Mansouri, A
Affuso, A
Arra, C
Macchia, V
Di Lauro, R
De Felice, M
机构
[1] CEINGE, Lab Anim Genet, Stn Zool Anton Dohrn, I-80145 Naples, Italy
[2] Univ Naples Federico II, Dipartimento Endocrinol & Oncol Mol & Clin, Naples, Italy
[3] Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol, Naples, Italy
[4] CEINGE, Biogem, Naples, Italy
[5] Inst Nazl Tumori Fdn Pascale, I-80131 Naples, Italy
[6] NCI, NIH, Lab Metab, Bethesda, MD 20892 USA
[7] Max Planck Inst Biophys Chem, Abt Mol Zellbiol, D-37077 Gottingen, Germany
关键词
D O I
10.1210/en.2005-0882
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:5038 / 5047
页数:10
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