Modifiers of a Mouse Model of Alagille Syndrome

描述（由申请人提供）：Alagille综合征是一种常染色体显性遗传疾病，其特征为肝脏、心脏、眼睛、骨骼和肾脏的发育异常。Alagille综合征是由于编码Notch家族跨膜受体配体的Jaggedl（Jag 1）基因的单倍不足。我们已经建立了Alagille综合征的小鼠模型。虽然靶向Jag 1无效等位基因的杂合小鼠不表现出患有Alagille综合征的人类的大多数表型特征，但Jag 1和Notch 2靶向突变的双杂合小鼠表现出与人类Alagille综合征患者相似的多种缺陷。 这些缺陷包括胆管缺乏、肾脏中的肾小球缺陷以及心脏中的心房和心室间隔缺损。我们已经鉴定了Jagl突变与Dill和Notchl基因突变之间的额外双杂合遗传相互作用。这些相互作用表明Jagl突变小鼠可用于致敏诱变筛选。我们还发现C3 H株中存在天然存在的遗传修饰剂，可以增强Jag 1杂合小鼠中发生的耳前庭缺陷并抑制眼睛缺陷。 我们提出了三个具体的目标，以确定和表征在这个系统中的遗传修饰。本发明的目的是：1）绘制眼和内耳中Jag 1杂合表型的C3 H遗传修饰物，并确定这些修饰物是否影响Jag 1/Notch 2 Alagille综合征模型的肝脏或肾脏表型; 2）对Jag 1杂合小鼠表型的化学诱导显性增强子进行致敏遗传筛选; 3）对化学诱导的Jag 1纯合突变小鼠胚胎致死性的隐性抑制因子进行致敏遗传筛选。这些研究将使我们能够创建更有代表性的小鼠模型的Alagille综合征，并应提供洞察变量表型表达观察Alagille综合征患者。

DESCRIPTION (provided by applicant): Alagille syndrome is an autosomal dominant disorder characterized by developmental abnormalities of the liver, heart, eye, skeleton and kidney. Alagille syndrome is due to haploinsufficiency for the Jaggedl (Jag1) gene, which encodes a ligand for the Notch family of transmembrane receptors. We have developed a mouse model of Alagille syndrome. While mice heterozygous for a targeted Jag1 null allele do not exhibit most phenotypes characteristic of humans with Alagille syndrome, mice doubly heterozygous for Jag1 and Notch2 targeted mutations exhibit multiple defects similar to human Alagille syndrome patients. These defects include bile duct paucity, glomerular defects in the kidneys, and atrial and ventricular septal defects in the heart. We have identified additional double heterozygous genetic interactions between the Jagl mutation and mutations in the Dill and Notchl genes. These interactions demonstrate that Jagl mutant mice could be used in sensitized mutagenesis screens. We also found that naturally occurring genetic modifiers exist in the C3H strain that enhance ear vestibular defects and suppress eye defects that occur in Jag1 heterozygous mice. We propose three specific aims to identify and characterize genetic modifiers in this system. The aims of this proposal are to: 1) map the C3H genetic modifiers of Jag1 heterozygous phenotypes in the eye and inner ear, and determine if these modifiers affect the liver or kidney phenotypes of the Jagl/Notch2 Alagille syndrome model; 2) perform a sensitized genetic screen for chemically-induced dominant enhancers of the phenotypes of Jag1 heterozygous mice; 3) perform a sensitized genetic screen for chemically-induced recessive suppressors of the embryonic lethality of Jag1 homozygous mutant mice. These studies will enable us to create more representative mouse models of Alagille syndrome, and should provide insight into the variable phenotypic expression observed in Alagille syndrome patients.