Neumann Susanne, Bayer Yvonne, Reske Andreas, Tajtáková Mária, Langer Pavel, Paschke Ralf
Third Medical Department, University of Leipzig, Ph.-Rosenthal-Strasse 27, 04103 Leipzig, Germany.
J Mol Med (Berl). 2003 Nov;81(11):736-45. doi: 10.1007/s00109-003-0463-6. Epub 2003 Oct 15.
Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also strongly indicate a genetic prediposition. In euthyroid goiters molecular defects in the thyroglobulin (TG), and Na+/I- symporter (NIS) gene have been identified. Numerous mutations in the Pendrin (PDS) gene have been found in families with PDS characterized by deafness and euthyroid goiter. Moreover, family studies indicated two major candidate loci MNG-1 on chromosome 14q31 and Xp22. However, all previous linkage studies investigated only one family. To clarify the general relevance of these previously identified two major candidate loci for the etiology of euthyroid goiter we investigated four families with a total number of 74 family members by linkage analysis with microsatellite markers. Moreover, we analyzed the thyroid candidate genes TG, thyroperoxidase (TPO), NIS, TSH receptor, and PDS. In a further family with 12 members in whom we have previously demonstrated linkage to the MNG-1 locus we investigated the Xp22 locus and the PDS gene in addition to our initial study. Linkage analysis results of our study are not significant enough to definitely exclude or confirm linkage to the investigated candidate genes and loci. Nevertheless, we obtained very weak indications for possible linkage to Xp22 in one family by a maximal multipoint LOD score of 1.15, and cosegregation of haplotypes among affected family members. Moreover, in another family linkage to PDS was indicated by a maximal multipoint LOD score of 1.87 as well as cosegregation of haplotypes. However, sequencing of the PDS gene did not reveal germline mutations. A significant total NPL score of 6.5 for PDS over all families most likely indicated linkage to a genomic region close to PDS. Furthermore, the likelihood of linkage to MNG-1 and Xp22 is reduced, because multipoint LOD scores were below 1 or negative. In all families there was no significant evidence for linkage for the thyroid candidate genes TG, TPO, NIS, or the TSH receptor. In conclusion, a general role of MNG-1 and Xp22 for the etiology of euthyroid goiter is unlikely but cannot clearly excluded. The multipoint parametric and nonparametric LOD scores further suggest genetic heterogeneity in the etiology of familial euthyroid goiter. To identify other susceptibility loci it is necessary to perform genome-wide linkage analysis studies with more families.
碘缺乏是甲状腺功能正常的地方性甲状腺肿最重要的病因。然而，家族研究和双胞胎研究也有力地表明存在遗传易感性。在甲状腺功能正常的甲状腺肿中，已发现甲状腺球蛋白（TG）和钠/碘同向转运体（NIS）基因存在分子缺陷。在以耳聋和甲状腺功能正常的甲状腺肿为特征的Pendrin（PDS）基因家族中发现了许多突变。此外，家族研究表明14q31染色体和Xp22上有两个主要候选基因座MNG-1。然而，以往所有的连锁研究仅调查了一个家族。为了阐明这些先前确定的两个主要候选基因座与甲状腺功能正常的甲状腺肿病因的普遍相关性，我们通过微卫星标记的连锁分析对4个家族共74名家庭成员进行了研究。此外，我们分析了甲状腺候选基因TG、甲状腺过氧化物酶（TPO）、NIS、促甲状腺激素受体和PDS。在另一个有12名成员的家族中，我们先前已证明其与MNG-1基因座连锁，除了最初的研究外，我们还研究了Xp22基因座和PDS基因。我们研究的连锁分析结果不够显著，无法明确排除或确认与所研究的候选基因和基因座的连锁关系。然而，我们在一个家族中通过最大多点对数优势分数为1.15以及受影响家庭成员间单倍型的共分离，获得了与Xp22可能连锁的非常微弱的迹象。此外，在另一个家族中，最大多点对数优势分数为1.87以及单倍型的共分离表明与PDS连锁。然而，PDS基因的测序未发现种系突变。所有家族中PDS的总非参数连锁分数为6.5，这很可能表明与靠近PDS的基因组区域连锁。此外，与MNG-1和Xp22连锁的可能性降低，因为多点对数优势分数低于1或为负数。在所有家族中，没有明显证据表明甲状腺候选基因TG、TPO、NIS或促甲状腺激素受体存在连锁。总之，MNG-1和Xp22在甲状腺功能正常的甲状腺肿病因中起普遍作用的可能性不大，但不能明确排除。多点参数和非参数对数优势分数进一步表明家族性甲状腺功能正常的甲状腺肿病因存在遗传异质性。为了确定其他易感基因座，有必要对更多家族进行全基因组连锁分析研究。
