HMSNL mutations - Research from Austrailia

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Abstract from Human Mutations. 2003 Aug;22(2):129-35.

Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in

patients with Charcot-Marie-Tooth Disease.

unter M, Bernard R, Freitas E, Boyer A, Morar B, s IJ, Tournev I,

Jordanova A, Guergelcheva V, Ishpekova B, Kremensky I, Nicholson G,

Schlotter B, Lochmuller H, Voit T, Colomer J, PK, Levy N,

Kalaydjieva L. Laboratory of Molecular Genetics, Western Australian

Institute for Medical Research and Centre for Medical Research, The

University of Western Australia, Nedlands, Australia.

In a previous study, we have shown that N-myc downstream-regulated gene

1 (NDRG1), classified in databases as a tumor suppressor and heavy

metal-response protein, is mutated in hereditary motor and sensory

neuropathy Lom (HMSNL), a severe autosomal recessive form of

Charcot-Marie-Tooth (CMT) disease. The private founder mutation

R148X, causing HMSNL in patients of Romani ethnicity, has so far

remained the only molecular defect linking NDRG1 to a specific disease

phenotype. Here we report the first study aiming 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. Sequence analysis of NDRG1 in 104 CMT patients 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. The phenotype of the IVS8-1G>A

homozygote was very closely related to that of HMSNL patients. In

addition, we have detected homozygosity for the known 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. No other variants were identified in the coding sequence,

whereas 12 single nucleotide polymorphisms were observed in the introns.