A Knockin Mouse Model for Oculopharyngeal Muscular Dystrophy

描述(申请人提供)：眼咽肌营养不良症(OPMD)是一种成人发病的疾病，以眼睑下垂和吞咽困难为特征，近端肢体肌肉也有虚弱的表现。这种疾病没有治愈的方法。导致这种疾病的突变是在聚腺苷结合蛋白核1(PABPN1)基因内发现的。广泛表达的PABPN1蛋白通过调节3‘端的形成，包括多聚(A)尾长和3’端的裂解/多聚腺苷酸化位点的选择来调节转录后基因的表达。OPMD的常染色体显性遗传形式是该病最常见的形式，其特征是蛋白质的N-末端结构域中的聚丙氨酸从正常的10个丙氨酸扩大到12-17个。常染色体显性遗传性OPMD患者有1个PABPN1突变等位基因和1个PABPN1正常等位基因。然而，目前的OPMD小鼠模型是转基因的，因此除了PABPN1的一个突变等位基因外，还含有两个正常的PABPN1等位基因，导致PABPN1的显著过度表达。因此，这些小鼠模型不能准确反映患有这种疾病的患者的基因型别。我们已经创建了一个敲入小鼠模型，该模型在Cre重组酶存在的情况下表达PABPN1，该模型包含17个丙氨酸的聚丙氨酸扩展(Ala17PABPN1)，因此与常染色体显性遗传OPMD患者的遗传变化更接近。这项建议的目的是彻底了解Ala17PABPN1对肌肉病理和功能的影响(目标1)，并开始检查这些Ala17PABPN1基因敲入小鼠的整个生命周期对RNA转录后加工(Aim 2)的影响。我们认为，这种新的小鼠模型对于未来了解突变的PABPN1的组织特异性后果和测试潜在的治疗方法将是非常有价值的。

DESCRIPTION (provided by applicant): Oculopharyngeal muscular dystrophy (OPMD) is an adult onset disease characterized by eyelid drooping and difficulties in swallowing, with weakness also noted in proximal limb muscles. No cure exists for this disease. The mutation responsible for the disease is found within the polyadenylate-binding protein nuclear 1 (PABPN1) gene. The ubiquitously expressed PABPN1 protein regulates post-transcriptional gene expression through modulating 3'-end formation including poly(A) tail length and 3'-end cleavage/polyadenylation site selection. The autosomal dominant form of OPMD, which is the most common form of the disease, is characterized by a polyalanine expansion in the N-terminal domain of the protein from the normal 10 alanines to 12-17. Patients with autosomal dominant OPMD have one mutant allele of PABPN1 and one normal allele of PABPN1. However, current mouse models of OPMD are transgenic and thus contain two normal alleles of PABPN1 in addition to one mutant allele of PABPN1 leading to significant overexpression of PABPN1. Thus, these mouse models do not accurately reflect the genotype of patients afflicted with the disease. We have created a knock- in mouse model that expresses PABPN1 containing a polyalanine expansion of 17 alanines (Ala17PABPN1) in the presence of Cre-recombinase and is thus more closely aligned with the genetic changes in autosomal dominant OPMD patients. The goal of this proposal is to thoroughly understand the effects of Ala17PABPN1 on muscle pathology and function (Aim 1) as well as to begin to examine the impact on post-transcriptional processing of RNA (Aim 2) throughout the lifespan of these Ala17PABPN1 knock-in mice. We propose that this new mouse model will be invaluable for future studies in understanding the tissue-specific consequences of mutant PABPN1 and testing potential therapies.