Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter

Iodine deficiency is the most important etiological factor for euthyroid en demic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na +/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gen e. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthy roid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO a nd TSH receptor genes revealed several previously reported polymorphisms. A s it is not possible to exclude a functional relevance for all polymorphism s, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multi point logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of lin kage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently ide ntified locus for familial multinodular nontoxic goiter (MNG-1) on chromoso me 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxi c goiter.