College of Animal Science, Xinjiang Agricultural University, Urumqi, Xinjiang, 830052, China; Key Laboratory of Ruminant Genetics, Breeding & Reproduction, Ministry of Agriculture, Key Laboratory of Animal Biotechnology of Xinjiang, Institute of Biotechnology, Xinjiang Academy of Animal Science, Urumqi, Xinjiang, 830011, China.
Key Laboratory of Ruminant Genetics, Breeding & Reproduction, Ministry of Agriculture, Key Laboratory of Animal Biotechnology of Xinjiang, Institute of Biotechnology, Xinjiang Academy of Animal Science, Urumqi, Xinjiang, 830011, China.
Gene. 2024 May 30;909:148307. doi: 10.1016/j.gene.2024.148307. Epub 2024 Feb 22.
Sheep congenital microtia is characterized by underdeveloped ears and provides an ideal basis for studying human microtia. This study identified the causal mutation and regulatory mechanisms underlying this disorder. Whole-genome association analysis was conducted using 23 ear tissue samples from sheep with microtia and 28 samples from normal-eared sheep. A significant correlation was found between microtia and a 76-base pair duplication in the enhancer region of the HMX1 gene. Further analysis of offspring phenotypes confirmed an autosomal dominant inheritance pattern. Genotypic analysis showed that individuals that are homozygous for this duplication were earless, heterozygous individuals exhibited shortened ears, and wild-type individuals had normal ears. Moreover, luciferase assays confirmed that this duplication increased HMX1 gene expression, and duplication knock-in mice also exhibited shorter and narrower external ears compared to wild-type mice. Transcriptomic analysis further demonstrated that this duplication enhanced HMX1 gene expression in animal models. This study characterized the causal regulatory mutation underlying sheep microtia.
绵羊先天性小耳畸形的特征是耳朵发育不良，为研究人类小耳畸形提供了理想的基础。本研究鉴定了导致这种疾病的突变和调控机制。对 23 个患有小耳畸形的绵羊耳部组织样本和 28 个正常耳部组织样本进行了全基因组关联分析。结果发现小耳畸形与 HMX1 基因增强子区域的 76 个碱基对重复之间存在显著相关性。对后代表型的进一步分析证实了常染色体显性遗传模式。基因型分析表明，该重复纯合子的个体无耳，杂合子个体的耳朵缩短，而野生型个体的耳朵正常。此外，荧光素酶检测证实该重复可增加 HMX1 基因的表达，并且重复敲入小鼠的外耳也比野生型小鼠更短、更窄。转录组分析进一步表明，该重复可增强动物模型中 HMX1 基因的表达。本研究对绵羊小耳畸形的致病调控突变进行了特征描述。
