HMSN/CMT L

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Biochem Biophys Res Commun. 2005 May 25;

NDRG1 interacts with APO A-I and A-II and is a functional candidate

for the HDL-C QTL on 8q24.

Hunter M, Angelicheva D, Tournev I, Ingley E, Chan DC, Watts GF,

Kremensky I, Kalaydjieva L.

Laboratory for Molecular Genetics, Western Australian Institute for

Medical Research and Centre for Medical Research, The University of

Western Australia, Nedlands 6009, Australia.

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.