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Molecular Investigations of the CMT4D Gene N-Myc Downstream-Regulated Gene 1(NDRG1)

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Molecular Investigations of the CMT4D Gene N-Myc Downstream-Regulated Gene 1(NDRG1) Molecular Investigations of the CMT4D Gene N-myc Downstream-Regulated Gene 1(NDRG1) Michael Hunter This thesis is presented for the degree of Doctor of Philosophy at The University of Western Australia Western Australian Institute for Medical Research And Centre for Medical Research School of Medicine and Pharmacology 2006 i ABSTRACT Hereditary Motor and Sensory Neuropathy Lom (HMSNL) is a severe autosomal recessive peripheral neuropathy, the most common form of demyelinating Charcot- Marie-Tooth (CMT) disease in the Roma (Gypsy) population. The mutated gene, N-myc downstream-regulated gene 1 (NDRG1) on chromosome 8q24, is widely expressed and has been implicated in a wide range of processes and pathways. In this study we have aimed to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded, as well as to gain clues about its function through the identification of its interactions with other proteins. Sequence analysis of NDRG1 in 104 patients with CMT disease and of diverse ethnicity identified one novel disease-causing mutation, IVS8- 1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. In addition, we have detected homozygosity for the known Roma R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. To gain an insight into NDRG1 function yeast two-hybrid screening of mouse sciatic nerve, human fetal brain and murine pluripotent cell line libraries were performed and identified interacting proteins whose known functions suggest NDRG1 involvement in cellular trafficking. Further analyses, focusing on apolipoproteins A-I (APOA1) and A-II (APOA2), confirmed their interaction with NDRG1 in mammalian cells. The results suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in CMT4D. At the same time, database searches showed that the chromosomal location of NDRG1 coincides with a reported High-Density Lipoprotein-Cholesterol Quantitive Trait Locus (HDL-C QTL) in humans and in mice. A putative role of NDRG1 in the general mechanisms of HDL-mediated cholesterol transport was supported by biochemical studies of blood lipids, which revealed an association between the Gypsy founder mutation, R148X, and decreased HDL-C levels. These findings suggest that while peripheral neuropathy is the drastic result of NDRG1 deficiency, the primary role of the protein may be related to general mechanisms of lipid transport/metabolism. ii TABLE OF CONTENTS ABSTRACT ............................................................................................................................. ii TABLE OF CONTENTS....................................................................................................... iii LIST OF TABLES ..................................................................................................................iv LIST OF FIGURES.................................................................................................................v ACKNOWLEDGEMENTS................................................................................................... vii DECLARATION OF CONTENT.......................................................................................... ix PUBLICATIONS ARISING FROM THIS THESIS ............................................................ x CHAPTER 1 – INTRODUCTION ......................................................................................... 1 1.1 GENERAL OVERVIEW OF CHARCOT-MARIE-TOOTH (CMT) DISEASE .............................. 1 1.2 HEREDITARY MOTOR AND SENSORY NEUROPATHY-LOM (HMSNL) ............................... 3 1.3 PROPOSED ROLES OF NDRG1 DERIVED FROM NON-NEURAL TISSUE AND CELL-TYPES .. 10 1.4 CURRENT KNOWLEDGE OF NDRG1 EXPRESSION AND POSSIBLE FUNCTION IN PERIPHERAL NERVE ............................................................................................................. 15 1.5 AIMS OF THIS PHD PROJECT .......................................................................................... 16 CHAPTER 2 – THE IDENTIFICATION OF NDRG1 MUTATIONS IN PATIENTS WITH CHARCOT-MARIE-TOOTH DISEASE ................................................................. 18 2.1 BACKGROUND............................................................................................................... 18 2.2 METHODS...................................................................................................................... 20 2.3 RESULTS .................................................................................................................... 26 2.4 DISCUSSION .................................................................................................................. 35 CHAPTER 3 – THE IDENTIFICATION OF NDRG1 PROTEIN-PARTNERS BY YEAST TWO-HYBRID LIBRARY SCREENING .............................................................. 39 3.1 BACKGROUND............................................................................................................... 39 3.2 METHODS...................................................................................................................... 44 3.3 RESULTS ....................................................................................................................... 59 3.4 DISCUSSION .................................................................................................................. 76 CHAPTER 4 - CONFIRMING NDRG1-PROTEIN INTERACTIONS ............................ 83 4.1 BACKGROUND............................................................................................................... 83 4.2 METHODS...................................................................................................................... 87 4.3 RESULTS ....................................................................................................................... 96 4.4 DISCUSSION ................................................................................................................ 115 CHAPTER 5 – EFFECT OF NDRG1 DEFICIENCY ON EXTRACELLULAR CHOLESTEROL TRANSPORT ........................................................................................ 124 5.1 BACKGROUND............................................................................................................. 124 5.2 METHODS.................................................................................................................... 127 5.3 RESULTS ..................................................................................................................... 129 5.4 DISCUSSION ................................................................................................................ 133 CHAPTER 6 - MOUSE MODELS OF NDRG1 DEFICIENCY..................................... 137 6.1 BACKGROUND............................................................................................................. 137 6.2 METHODS.................................................................................................................... 140 6.3 RESULTS ..................................................................................................................... 143 6.4 DISCUSSION ................................................................................................................ 150 CHAPTER 7 – SUMMARY AND CONCLUDING DISCUSSION.................................. 152 REFERENCES................................................................................................................... 156 iii LIST OF TABLES Table 1.1 Genes and loci implicated in different forms of CMT disease and their modes of inheritance ................................................................................................................... 2 Table 1.2. Conditions and agents regulating NDRG1 expression.......................................... 11 Table 2.1. Incidence of mutations in common CMT genes determined from large cohort screening of CMT patients............................................................................................. 18 Table 2.2. Primers used in the cDNA analysis of sequence variants potentially affecting RNA splicing ................................................................................................................. 24 Table 2.3. Single nucleotide polymorphisms in NDRG1 in 104 unrelated Caucasian individuals with CMT disease ....................................................................................... 29 Table 2.4. Nucleotide diversity in NDRG1............................................................................ 31 Table 3.1. NDRG1-LexBD interactors detected by yeast two-hybrid screening of a murine pluripotent cell line (EML C.1) ......................................................................... 41 Table 3.2 False positive interactors identified from yeast two-hybrid screening of human fetal brain and mouse sciatic nerve libraries.................................................................. 63 Table 3.3. Candidate NDRG1 interactors identified from yeast two-hybrid screening in nerve tissue..................................................................................................................... 64 Table 3.4. PRA1-protein partners identified from yeast two-hybrid screens ........................ 79 Table 5.1. Blood lipid parameters
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