Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease.

Abstract

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. Hum Mutat 22:129-135, 2003.

• Authors: Michael Hunter, Rafaëlle Bernard, Elizabeth Freitas, Amandine Boyer, Bharti Morar, Ian J Martins, Ivailo Tournev, Albena Jordanova, Velina Guergelcheva, Boryana Ishpekova, Ivo Kremensky, Garth Nicholson, Beate Schlotter, Hanns Lochmüller, Thomas Voit, Jaume Colomer, P K Thomas, Nicolas Levy, Luba Kalaydjieva
• Journal: Human mutation (Hum Mutat) Vol. 22 Issue 2 Pg. 129-35 (Aug 2003) ISSN: 1098-1004 [Electronic] United States
• PMID: 12872253 (Publication Type: Journal Article)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Cell Cycle Proteins
• Intracellular Signaling Peptides and Proteins
• N-myc downstream-regulated gene 1 protein
• RNA Splice Sites

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Alternative Splicing (genetics)
• Cell Cycle Proteins (genetics)
• Charcot-Marie-Tooth Disease (genetics)
• Child
• Child, Preschool
• DNA Mutational Analysis (methods)
• Female
• Humans
• Infant
• Intracellular Signaling Peptides and Proteins
• Male
• Middle Aged
• Mutation, Missense (genetics)
• Polymorphism, Single Nucleotide (genetics)
• RNA Splice Sites (genetics)