A Knockin Mouse Model for Oculopharyngeal Muscular Dystrophy

描述（由申请人提供）：眼咽肌营养不良症（OPMD）是一种成人发病疾病，其特征是眼睑下垂和吞咽困难，同时近端肢体肌肉也出现无力。这种病无药可治。导致这种疾病的突变存在于多聚腺苷酸结合蛋白核1（PABPN 1）基因中。广泛表达的PABPN 1蛋白通过调节3 '端形成（包括poly（A）尾长和3'端切割/聚腺苷酸化位点选择）来调节转录后基因表达。OPMD的常染色体显性形式是该疾病的最常见形式，其特征在于蛋白质的N-末端结构域中的聚丙氨酸从正常的10个丙氨酸扩展到12-17个。患有常染色体显性OPMD的患者具有PABPN 1的一个突变等位基因和PABPN 1的一个正常等位基因。然而，目前的OPMD小鼠模型是转基因的，因此除了PABPN 1的一个突变等位基因之外还含有PABPN 1的两个正常等位基因，导致PABPN 1的显著过表达。因此，这些小鼠模型不能准确地反映患有该疾病的患者的基因型。我们已经创建了在Cre重组酶存在下表达含有17个丙氨酸的聚丙氨酸扩增（Ala 17 PABPN 1）的PABPN 1的敲入小鼠模型，因此与常染色体显性OPMD患者中的遗传变化更紧密地一致。本提案的目标是彻底了解Ala 17 PABPN 1对肌肉病理和功能的影响（目标1），以及开始检查这些Ala 17 PABPN 1敲入小鼠整个寿命期间对RNA转录后加工的影响（目标2）。我们建议，这种新的小鼠模型将是非常宝贵的未来研究在理解组织特异性后果的突变PABPN 1和测试潜在的治疗。

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.