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15q26.1 上的 TTTG 微卫星中的功能变体导致家族性非自身免疫性甲状腺异常。

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

机构信息

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

出版信息

Nat Genet. 2024 May;56(5):869-876. doi: 10.1038/s41588-024-01735-5. Epub 2024 May 7.

DOI:10.1038/s41588-024-01735-5
PMID:38714868
原文链接:
https://pmc.ncbi.nlm.nih.gov/articles/PMC11096107/
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.

摘要

新生儿甲状腺激素产生不足称为先天性甲状腺功能减退症。多结节性甲状腺肿（MNG）的特征是甲状腺肿大并有多个结节，通常见于成年人，被认为是与先天性甲状腺功能减退症不同的独立疾病。在这里，我们对一个同时患有非甲状腺肿先天性甲状腺功能减退症和 MNG 的家族进行了连锁分析，在 15q26.1 处发现了一个信号。对先天性甲状腺功能减退症和 MNG 队列进行全基因组测序和遗传筛选的后续分析表明，与对照组（3/38722）相比，15q26.1 上的非编码 TTTG 微卫星在先天性甲状腺功能减退症（989 例中有 137 例）和 MNG（3 例中有 3 例）中经常发生变化。利用表观基因组数据和体外实验对非编码变异进行特征分析表明，微卫星位于甲状腺特异性转录抑制剂中，其活性被变异所破坏。总之，我们提供了将非甲状腺肿先天性甲状腺功能减退症和 MNG 联系起来的遗传证据，为甲状腺异常提供了独特的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/a5a6d49c1992/41588_2024_1735_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/9a37188c874b/41588_2024_1735_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/fba054c49164/41588_2024_1735_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/6fccd13e8fba/41588_2024_1735_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/db4c47d7f043/41588_2024_1735_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/a5a6d49c1992/41588_2024_1735_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/ed468a8b5054/41588_2024_1735_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/e7ad3d44394d/41588_2024_1735_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/7124d81c1860/41588_2024_1735_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/ad00349dfd90/41588_2024_1735_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/089324477ca6/41588_2024_1735_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/3f875f2ead22/41588_2024_1735_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/de8ad651f4eb/41588_2024_1735_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/9a37188c874b/41588_2024_1735_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/fba054c49164/41588_2024_1735_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/6fccd13e8fba/41588_2024_1735_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/db4c47d7f043/41588_2024_1735_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933c/11096107/a5a6d49c1992/41588_2024_1735_Fig12_ESM.jpg

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