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病，以肝脏、心脏、眼睛、骨骼和肾脏发育异常为特征。Alagille综合征是由于Jaggedl （Jag1）基因的单倍不足，该基因编码跨膜受体Notch家族的配体。我们开发了一种阿拉吉尔综合症的小鼠模型。靶Jag1零等位基因杂合的小鼠不表现出Alagille综合征患者的大多数表型特征，而靶Jag1和Notch2突变双杂合的小鼠表现出与人类Alagille综合征患者相似的多种缺陷。这些缺陷包括胆管缺乏、肾脏肾小球缺损、心脏房间隔缺损和室间隔缺损。我们已经确定了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，C3H菌株中存在自然发生的遗传修饰因子，可以增强Jag1杂合小鼠的耳前庭缺陷，抑制眼睛缺陷。

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.