日本庆应义塾大学医学院Satoshi Narumi团队近日取得一项新成果。经过不懈努力，他们发现15q26.1上TTTG微卫星功能突变导致家族性非自身免疫性甲状腺异常。该项研究成果发表在2024年5月7日出版的《自然-遗传学》上。

研究人员对一个同时患有先天性甲状腺功能衰退症和多结节性甲状腺肿（MNG）的家族进行了连锁分析，在15q26.1处发现了一个位点。对先天性甲状腺功能衰退症和MNG群体进行的全基因组测序和基因筛查后续分析表明，与对照组（38722例中有3例）相比，先天性甲状腺功能减退症（989例中有137例）和MNG（33例中有3例）患者15q26.1上的非编码TTTG微卫星经常发生变化。

利用表观基因组数据和体外实验对这些非编码变异进行特征描述，研究发现该微卫星位于甲状腺特异性转录抑制因子中，这些变异会破坏其活性。总之，该研究提出了先天性甲状腺功能减退症与MNG相关的遗传学证据，为甲状腺异常的发生提供了独特见解。

据了解，新生儿甲状腺激素分泌不足认为是先天性甲状腺功能减退症。MNG具有甲状腺肿大且有多个结节等特征，通常见于成人，是一种不同于先天性甲状腺功能减退症的疾病。

附：英文原文

Title: Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities

Author: Narumi, Satoshi, Nagasaki, Keisuke, Kiriya, Mitsuo, Uehara, Erika, Akiba, Kazuhisa, Tanase-Nakao, Kanako, Shimura, Kazuhiro, Abe, Kiyomi, Sugisawa, Chiho, Ishii, Tomohiro, Miyako, Kenichi, Hasegawa, Yukihiro, Maruo, Yoshihiro, Muroya, Koji, Watanabe, Natsuko, Nishihara, Eijun, Ito, Yuka, Kogai, Takahiko, Kameyama, Kaori, Nakabayashi, Kazuhiko, Hata, Kenichiro, Fukami, Maki, Shima, Hirohito, Kikuchi, Atsuo, Takayama, Jun, Tamiya, Gen, Hasegawa, Tomonobu

Issue&Volume: 2024-05-07

Abstract: Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

DOI: 10.1038/s41588-024-01735-5

Source: https://www.nature.com/articles/s41588-024-01735-5