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.

Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3

“…An increase in granulin, a human glioma-associated growth factor gene (Liau et al, 2000), might indicate the possibility that tumor cells might try to escape from cell death by stimulating their growth. As responses to external stimulus, several genes including N-myc downstream regulated gene 1, which was classified in databases as a tumor suppressor (Hunter et al, 2003), and heavy metal-response protein were upregulated. Upregulation of microtubule-associated protein light chain 3B among cell growth and/or maintenance-related genes indicated activation of autophagic pathway (Kabeya et al, 2000).…”

The Expression and Localization of N-Myc Downstream-Regulated Gene 1 in Human Trophoblasts

“…The expression of NDRG1 in murine Schwann cells is enhanced during regeneration after sciatic nerve injury [11]. These findings are attributed to a stop codon non-sense mutation (R148X) [12] or to an exon-9-skipping mutation (IVS8-1G>A, S181-K198) [13] found in humans with hereditary motor and sensory neuropathy-Lom (HMSNL, also known as Charcot-Marie-Tooth type 4D disease). This disease is characterized by Schwann cell demyelination and concomitant early axonal impairment affecting both motor and sense peripheral nerves, and resulting in a loss of limb muscle function and touch sensation in adulthood [12,13].…”

Differentiation-Related Gene-1 Decreases Bim Stability by Proteasome-Mediated Degradation

“…The gene for Drg1 has been localized to the chromosome 8q24.3 (8). Mutations in the Drg1 gene are linked to hereditary motor sensory neuropathy (9, 10) and Drg1-deficient mice exhibited a progressive demyelination of peripheral nerves (11). Several in vitro studies indicated this gene to be the target of multiple regulatory pathways.…”