Linkage of Familial Euthyroid Goiter to the Multinodular Goiter-1 Locus and Exclusion of the Candidate Genes Thyroglobulin, Thyroperoxidase, and Na+/I− Symporter*

Abstract

Iodine deficiency is the most important etiological factor for euthyroid endemic 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 gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, 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 multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage 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 identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.

Localization of a Susceptibility Gene for Familial Nonmedullary Thyroid Carcinoma to Chromosome 2q21

“…Multipoint HLOD and NPL scores across 2q21, using the complete set of 80 families and the 17 families with at least one case of fvPTC (with heterogeneity held at 0.42 and 0.80, respectively). studies of testicular cancer and multinodular goiter have used stratification by clinical criteria to detect areas of linkage (Bignell et al 1997;Neumann et al 1999;Rapley et al 2000). A review of the histopathology from the Tas1 family revealed that at least four of the eight PTC patients presented with the follicular variant of PTC (fvPTC) (Burgess et al 1997;authors' unpublished data), a recognized histological subtype (Hedinger et al 1988).…”

Follicular Neoplasm of Thyroid Revisited: Current Differential Diagnosis and the Impact of Molecular Testing

“…Large follicles with abundant colloid often have high rates of thyroglobulin (TG) synthesis and colloid production and low rates of endocytosis and hormone release. Although the precise mechanisms for hyperplastic growth have been elusive, environmental factors and a number of candidate genes, such as TG, TPO, NIS, TSHR , and MNG have been implicated 14,15. In general, NH may be further subclassified into multinodular (sporadic), endemic (often due to iodine deficiency), dyshormonogenetic (often due to mutations in TPO, TG , or DUOX2 genes resulting in continuous thyroid-stimulating hormone stimulation), and toxic (often associated with TSHR or GNAS mutation) types 16…”

“…Although the precise mechanisms for hyperplastic growth have been elusive, environmental factors and a number of candidate genes, such as TG, TPO, NIS, TSHR, and MNG have been implicated. 14,15 In general, NH may be further subclassified into multinodular (sporadic), endemic (often due to iodine deficiency), dyshormonogenetic (often due to mutations in TPO, TG, or DUOX2 genes resulting in continuous thyroid-stimulating hormone stimulation), and toxic (often associated with TSHR or GNAS mutation) types. 16 In contrast, thyroid follicular-patterned neoplasms are monoclonal processes that arise from single cells.…”

Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

“…Several studies suggest that AIHA is a forme fruste, the first isolated clinical presentation, of SLE in these patients (44,47,48 Studies of testicular cancer, multinodular goiter, and nonmedullary thyroid carcinoma already have revealed the power stratifying pedigrees by clinical manifestations has to detect previously unknown genetic linkages (49)(50)(51)(52). Kokori et al (53) suggested that AIHA may identify a particular subgroup of SLE patients because of an observed association with certain characteristic serologic and clinical manifestations.…”