N-myc Downstream-Regulated Gene 1 Is Mutated in Hereditary Motor and Sensory Neuropathy–Lom

Abstract

Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused research on the mechanisms of early development, cell differentiation, and cell-cell interactions in the peripheral nervous system. Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT, and understanding their molecular basis may provide a new perspective on these mechanisms. Here we report the identification of the gene responsible for hereditary motor and sensory neuropathy-Lom (HMSNL). HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis. The gene was previously mapped to 8q24.3, where conserved disease haplotypes suggested genetic homogeneity and a single founder mutation. We have reduced the HMSNL interval to 200 kb and have characterized it by means of large-scale genomic sequencing. Sequence analysis of two genes located in the critical region identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1). NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. We have studied expression in peripheral nerve and have detected particularly high levels in the Schwann cell. Taken together, these findings point to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann-cell signaling necessary for axonal survival.

N-myc Regulates Parkin Expression

“…However, additional studies that more directly measure parkin's effect on tumorigenesis now seem warranted. Another gene down-regulated by N-myc with a similar expression profile to parkin, NDRG1 (N-myc down-regulated gene 1), is involved in growth arrest and cell differentiation and is mutated in hereditary motor and sensory neuropathy-Lom (27). The involvement of autosomal-recessive loss of function mutations in NDRG1 in human peripheral neuropathy may be all the more relevant to parkin-linked disease, in that loss-offunction parkin mutations have also been identified in human patients with peripheral and sensory neuropathy (28,29).…”

NDRG4 Protein-deficient Mice Exhibit Spatial Learning Deficits and Vulnerabilities to Cerebral Ischemia

“…Overexpression of NDRG1 suppresses the metastatic potency of some types of cancer cells (4) and enhances the degranulation of mast cells in response to various stimuli (7). A nonsense mutation of NDRG1 causes hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease type 4D, which presents as distal muscle wasting and atrophy, foot and hand deformities, tendon areflexia, sensory loss, and deafness in afflicted individuals (8). We previously generated NDRG1-deficient mice and revealed the essential role of NDRG1 in the cytoplasm of Schwann cells for the maintenance of myelin sheaths in peripheral nerves (9).…”

Akt Mediates Insulin-stimulated Phosphorylation of Ndrg2

“…Ndrg1 (also called Drg1/Cap43/rit42/ TDD5/Ndr1), which is the most widely expressed and best characterized member, is mutated in hereditary motor and sensory neuropathy-Lom, a form of Charcot-Marie Tooth disease (7). The expression of Ndrg1 is inhibited by N-Myc (8), and the protein is repressed in transformed cells and up-regulated in growth-arrested differentiating cells (9).…”