Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome.

Background & Aims: Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in , resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.

Microarray data reveal relationship between Jag1 and Ddr1 in mouse liver.

Alagille syndrome is an autosomal dominant disorder involving bile duct paucity and cholestasis in addition to cardiac, skeletal, ophthalmologic, renal and vascular manifestations. Mutations in JAG1, encoding a ligand in the Notch signaling pathway, are found in 95% of patients meeting clinical criteria for Alagille syndrome. In order to define the role of Jag1 in the bile duct developmental abnormalities seen in ALGS, we previously created a Jag1 conditional knockout mouse model.

Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype.

Unlabelled: Alagille syndrome (AGS) is a heterogeneous developmental disorder associated with bile duct paucity and various organ anomalies. The syndrome is caused by mutations in JAG1, which encodes a ligand in the Notch signaling pathway, in the majority of cases and mutations in the NOTCH2 receptor gene in less than 1% of patients. Although a wide array of JAG1 mutations have been identified in the AGS population, these mutational variants have not accounted for the wide phenotypic variability observed in patients with this syndrome.

Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage.

Unlabelled: The Notch signaling pathway is involved in determination of cell fate and control of cell proliferation in multiple organ systems. Jag1 encodes a ligand in the Notch pathway and has been identified as the disease-causing gene for the developmental disorder Alagille syndrome. Evidence from the study of human disease and mouse models has implicated Jag1 as having an important role in the development of bile ducts.

Nondisjunction and transmission ratio distortion ofChromosome 2 in a (2.8) Robertsonian translocation mouse strain.

Aneuploidy results from nondisjunction of chromosomes in meiosis and is the leading cause of developmental disabilities and mental retardation in humans. Therefore, understanding aspects of chromosome segregation in a genetic model is of value. Mice heterozygous for a (2.

A novel variant of Inpp5f is imprinted in brain, and its expression is correlated with differential methylation of an internal CpG island.

Using a tissue-specific microarray screen in combination with chromosome anomalies in the mouse, we identified a novel imprinted gene, Inpp5f_v2 on mouse chromosome 7. Characterization of this gene reveals a 3.2-kb transcript that is paternally expressed in the brain.

Transmission ratio distortion in offspring of mouse heterozygous carriers of a (7.18) Robertsonian translocation.

Transmission ratio distortion (TRD) is defined as a significant departure from expected Mendelian ratios of inheritance of an allele or chromosome. TRD is observed among specific regions of the mouse and human genome and is frequently associated with chromosome rearrangements such as Robertsonian (Rb) chromosomes. We intercrossed mice heterozygous for a (7.

Translin-associated factor X is post-transcriptionally regulated by its partner protein TB-RBP, and both are essential for normal cell proliferation.

To determine the functions of the DNA/RNA-binding protein TB-RBP in somatic cells, we examined cultured primary mouse embryonic fibroblasts (MEFs) derived from TB-RBP-deficient mice. The TB-RBP-deficient MEFs exhibit a reduced growth rate compared with MEFs from littermates. Reintroduction of TB-RBP remedies this defect.

An Application of Molecular Genotyping in Mice.

Microsatellite markers are simple sequence repeats within the mammalian genome that can be used for identifying disease loci, mapping genes of interest as well as studying segregation patterns related to meiotic nondisjunction. Different strains of mice have variable CA repeat lengths and PCR based methods can be used to identify them, thus allowing for specific genotypes to be assigned. Molecular genotyping offers such identification at any developmental stage, which allows for a broad range of anomalies to be studied.

Molecular analysis of nondisjunction in mice heterozygous for a Robertsonian translocation.

A Robertsonian translocation results in a metacentric chromosome produced by the fusion of two acrocentric chromosomes. Rb heterozygous mice frequently generate aneuploid gametes and embryos, providing a good model for studying meiotic nondisjunction. We intercrossed mice heterozygous for a (7.