Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant inherited disease, characterized by germ-line mutations in the RET proto-oncogene, mainly in exons 10 and 11, but also in exons 13, 14 and 15. Recently, there were described also mutations in exon 8 and 16 associated with FMTC. In our laboratory the screening of six risk exons of the RET proto-oncogene in 141 families with MTC was performed. 10 families were classified as clinically FMTC. In 4 of them mutations in exons 11, 13 and 14 were detected. In the remaining families the screening of other RET exons has been started. For rapid RET proto-oncogene mutation screening we used single strand conformation polymorphism (SSCP) method and fluorescent sequencing method. Here we report a novel missense point mutation of the RET proto-oncogene in exon 5 that substitutes glycine for arginine at codon 321 in the cadherin-like domain in the extracellular region of ret protein found in one Czech family with FMTC. It is likely that this mutation causes familial medullary thyroid carcinoma (FMTC), because no other mutation was found in classical risk exons (10, 11, 13, 14, 15 and 16) of the RET proto-oncogene. The mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in two patients, two other family members are mutation carriers but still without clinical signs of MTC. Three other relatives are not mutation carriers and they are clinically unaffected. It seems that this newly described mutation belongs to less aggressive mutations with regard to later onset of the disease in index patient. To improve the diagnosis of FMTC, analysis of exon 5 of the RET proto-oncogene should be considered in families with unidentified classical RET mutations. The work was supported by grant IGA MZ CR NR/7806-3 and was approved by local Ethical committee.
01 - 05 Apr 2006
European Society of Endocrinology