Studies on rare diseases are important because they help to unravel the underlying mechanisms of diseases which may lead to novel therapies for patients. These efforts also offer rare opportunities to discover novel biological processes with major significance in biomedical research. This application is designed to explore a unique genotype-phenotype relationship based on a patient who is enrolled in the NIH Undiagnosed Disease Program (UDP). The patient harbors two compound heterozygous missense mutations in the CHML gene, with one mutant allele inherited from each parent. The patient exhibits developmental regression and neurodegeneration, including progressive cortical and white matter loss. The abnormal phenotypes are absent in the patient's siblings, who do not carry either mutation, and in their parents. In humans and other mammals, the paralogous genes CHM and CHML code for the Rab escort proteins REP-1 and REP-2, respectively. The Rab family consists of a large number of GTPases, which regulate complex membrane trafficking events. Posttranslational prenylation is required for targeting Rabs to specific subcellular membranes. REPs are essential for appropriate prenylation of Rabs. In zebrafish, there is only a single REP-coding gene, chm, and a nonsense mutation of the gene leads to degeneration of multiple organs. Extensive functional studies have been carried out on mammalian CHM orthologs. Null and missense mutations of CHM lead to degeneration of tissues in the eyes of patients with choroideremia. It has been proposed that tissues outside of the eyes in these patients, such as brain tissues, are likely protected by CHML. However, surprisingly, there are almost no functional studies of CHML orthologs despite their perceived importance until the first evidence of the impact of CHML from this UDP case. In this application, we propose to be the first group to test the related major hypothesis that CHML is an indispensable protector of brain tissues from degeneration using mouse mutations of Chml based on its high conservation with the human ortholog.
In Aim 1, we will engineer Chml null alleles and the UDP patient-specific missense mutations in mice.
In Aim 2, we will analyze the phenotypic consequences of compound heterozygosity of the missense mutations and the null alleles as loss-of-function controls. Phenotypic characterizations will include magnetic resonance imaging (MRI) and stereology analysis of brain structures as well as behavioral analysis of motor and cognitive functions. We will also analyze Rab prenylation in the mutant mice to explore the mechanistic link between genotypes and phenotypes. The success of this project will reveal for the first time the essential role of CHML in maintaining the integrity of the central nervous system, thereby laying the mechanistic foundation for future studies on the UDP patient, including therapeutic studies. The success of this project will also open up possibilities that CHML mutations and CHML-associated biological processes may play critical roles in other neurodegenerative disorders as well as autism spectrum disorder in which developmental regression is an important clinical feature.
This project will model patient-associated genetic alterations of the CHML gene identified by the NIH Undiagnosed Disease Program (UDP) with the goal to establish the causal relationship between the mutations and the phenotypes of developmental regression and neurodegeneration. The attainment of the proposed objectives will lead to identification of novel biological processes for maintaining integrity of the central nervous system and preventing neurodegeneration. The information generated from this project will enhance our understanding of molecular mechanisms underlying not only the rare disorder but also common diseases associated with developmental regression, such as autism spectrum disorder, and neurodegeneration, which in turn will benefit the efforts to develop novel therapeutic interventions for these diseases.
| Liu, Chunhong; Yu, Tao; Xing, Zhuo et al. (2018) Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors. Oncotarget 9:4773-4786 |
| Herault, Yann; Delabar, Jean M; Fisher, Elizabeth M C et al. (2017) Rodent models in Down syndrome research: impact and future opportunities. Dis Model Mech 10:1165-1186 |
| Xing, Zhuo; Li, Yichen; Pao, Annie et al. (2016) Mouse-based genetic modeling and analysis of Down syndrome. Br Med Bull 120:111-122 |
| Jiang, Xiaoling; Liu, Chunhong; Yu, Tao et al. (2015) Genetic dissection of the Down syndrome critical region. Hum Mol Genet 24:6540-51 |
