Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes.
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.
Castanet
Mireille
M
INSERM U457, Hôpital Robert Debré, Paris, France.
Sura-Trueba
Sylvia
S
Chauty
Anne
A
Carré
Aurore
A
de Roux
Nicolas
N
Heath
Simon
S
Léger
Juliane
J
Lyonnet
Stanislas
S
Czernichow
Paul
P
Polak
Michel
M
D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000503:physiopathology; D008126:Lod Score; D008297:Male; D010375:Pedigree; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors