NDRG1 interacts with APO A-I and A-II and is a functional candidate for the HDL-C QTL on 8q24.
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), is widely expressed and has been implicated in a range of processes and pathways. To gain an insight into NDRG1 function we performed yeast two-hybrid screening and identified interacting proteins whose known functions suggest involvement in cellular trafficking. Further analyses, focusing on apolipoproteins A-I and A-II, confirmed their interaction with NDRG1 in mammalian cells and suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in HMSNL. At the same time, the chromosomal location of NDRG1 coincides with a reported 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.
Hunter
Michael
M
Laboratory for Molecular Genetics, Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands 6009, Australia.
Angelicheva
Dora
D
Tournev
Ivailo
I
Ingley
Evan
E
Chan
Dick C
DC
Watts
Gerald F
GF
Kremensky
Ivo
I
Kalaydjieva
Luba
L
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D016633:Apolipoprotein A-II / Q000378:metabolism*; D019556:COS Cells; D018797:Cell Cycle Proteins; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8; D018076:DNA, Complementary / Q000378:metabolism; D004735:Energy Transfer; D018703:Founder Effect; D015723:Gene Library; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D040641:Quantitative Trait Loci; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D018797:Cell Cycle Proteins; D002784:Cholesterol; D008076:Cholesterol, HDL; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D011506:Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein