N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom

Am J Hum Genet. 2000 Jul;67(1):47-58. doi: 10.1086/302978. Epub 2000 May 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Base Sequence
  • CCN Intercellular Signaling Proteins
  • Cell Cycle Proteins*
  • Cells, Cultured
  • Chromosomes, Human, Pair 8 / genetics
  • Codon, Terminator / genetics
  • Conserved Sequence / genetics
  • Contig Mapping
  • DNA Mutational Analysis
  • Exons / genetics
  • Founder Effect
  • Genetic Linkage / genetics
  • Growth Substances / genetics
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Humans
  • Hybrid Cells
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Oncogene Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Schwann Cells / metabolism


  • CCN Intercellular Signaling Proteins
  • CCN4 protein, human
  • Cell Cycle Proteins
  • Codon, Terminator
  • Growth Substances
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger

Associated data

  • GENBANK/AB033074
  • GENBANK/AB033921
  • GENBANK/AB033922
  • GENBANK/AF045564
  • GENBANK/AF145594
  • GENBANK/AF159092
  • GENBANK/AF186190
  • GENBANK/AF189148
  • GENBANK/AF192304
  • GENBANK/AF230380
  • GENBANK/AL031662
  • GENBANK/D87953