Sloop K W, Parker G E, Hanna K R, Wright H A, Rhodes S J
Department of Biology, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, 46202-5132, Indianapolis, IN, USA.
Gene. 2001 Mar 7;265(1-2):61-9. doi: 10.1016/s0378-1119(01)00369-9.
The Lhx3 LIM homeodomain transcription factor is critical for pituitary gland formation and specification of the anterior pituitary hormone-secreting cell types. Two mutations in LHX3, a missense mutation changing a tyrosine to a cysteine and an intragenic deletion that results in a truncated protein lacking the DNA-binding homeodomain, have been identified in humans. These mutations were identified in patients with retarded growth and combined pituitary hormone deficiency and also abnormal neck and cervical spine development. For both the LHX3a and LHX3b isoforms, we compared the ability of wild type and mutant LHX3 proteins to trans-activate pituitary genes, bind DNA recognition elements, and interact with partner proteins. The tyrosine missense mutation inhibits the ability of LHX3 to induce transcription from selected target genes but does not prevent DNA binding and interaction with partner proteins such as NLI and Pit-1. Mutant LHX3 proteins lacking a homeodomain do not bind DNA and do not induce transcription from pituitary genes. These studies demonstrate that mutations in the LHX3 isoforms impair their gene regulatory functions and support the hypothesis that defects in the LHX3 gene cause complex pituitary disease in humans.
Lhx3 LIM 同源结构域转录因子对于垂体形成以及腺垂体激素分泌细胞类型的特异性分化至关重要。在人类中已鉴定出 LHX3 的两种突变，一种是错义突变，将酪氨酸变为半胱氨酸，另一种是基因内缺失，导致产生一种缺少 DNA 结合同源结构域的截短蛋白。这些突变在生长发育迟缓、合并垂体激素缺乏以及颈部和颈椎发育异常的患者中被发现。对于 LHX3a 和 LHX3b 两种亚型，我们比较了野生型和突变型 LHX3 蛋白激活垂体基因转录、结合 DNA 识别元件以及与伴侣蛋白相互作用的能力。酪氨酸错义突变抑制了 LHX3 从选定靶基因诱导转录的能力，但不影响其与 DNA 的结合以及与诸如 NLI 和 Pit-1 等伴侣蛋白的相互作用。缺少同源结构域的突变型 LHX3 蛋白不结合 DNA，也不诱导垂体基因的转录。这些研究表明，LHX3 亚型中的突变损害了它们的基因调控功能，并支持了 LHX3 基因缺陷导致人类复杂垂体疾病的假说。
