Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

被引:30
作者
Castanet, M
Sura-Trueba, S
Chauty, A
Carré, A
de Roux, N
Heath, S
Léger, J
Lyonnet, S
Czernichow, P
Polak, M
机构
[1] Hop Necker Enfants Malad, Paediat Endocrinol Unit, INSERM EMI 0363, F-75015 Paris, France
[2] Hop Robert Debre, INSERM, U457, F-75019 Paris, France
[3] Hop Necker Enfants Malad, INSERM, U584, F-75015 Paris, France
[4] Hop Bicetre, Dept Hormonol & Mol Biol, Le Kremlin Bicetre, France
[5] Natl Ctr Genotyping CNG, Evry, France
[6] Hop Robert Debre, Pediat Endocrine Unit, F-75019 Paris, France
[7] Hop Necker Enfants Malad, INSERM, U393, Paris, France
[8] Hop Necker Enfants Malad, Pediat Endocrine Unit, Paris, France
关键词
thyroid dysgenesis; familial disorder; TTF1; TTF2; Pax8; TSHR;
D O I
10.1038/sj.ejhg.5201321
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The pathophysiology of thyroid dysgenesis (TD) is not elucidated yet in the majority of cases. The unexpected familial clustering of congenital hypothyroidism due to TD suggests a genetically determined disorder. Four genes have been hitherto involved in thyroid development, including migration and growth. Three of these encode transcription factors ( the thyroid transcription factors 1 and 2 (TTF1 or NKX2.1 and TTF2 or FOXE1) and PAX8) while the other encodes the thyrotropin hormone receptor (TSHR). Some mutations have been reported in patients affected by thyroid defects, which supports the relevance of these four genes in TD. However, their involvement in the general TD population remains questionable. Therefore, to document their involvement, we performed a linkage analysis followed by mutational analysis in 19 multiplex TD families. The LOD score results failed to prove linkage between any of the four genes and the TD phenotype, whatever the postulated mode of inheritance. Manual extended haplotypes showed allele sharing among affected individuals of at least one of these four genes in the majority of families. Nevertheless, mutational analysis did not identify mutations in these cases, arguing in favor of identity by descent and not identity by state. Furthermore, as a main result of the present study, extended haplotypes confirmed by mutational analysis showed that the four genes were excluded in five out of the 19 investigated families, demonstrating the relevance of other genes. In conclusion, the present study demonstrates genetic heterogeneity in the TD disorder and suggests the involvement of novel genes.
引用
收藏
页码:232 / 239
页数:8
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