Neuropathy target esterase gene mutations cause motor neuron disease

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Shirley Rainier1, Melanie Bui, Erin Mark

  • 1Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

American Journal of Human Genetics
|March 4, 2008
PubMed

Insights

Mutations in the neuropathy target esterase (NTE) gene cause motor neuron disease (MND) and axonal degeneration. This finding suggests NTE pathway dysfunction may contribute to other neurodegenerative conditions like ALS.

Area of Science:

  • Neuroscience
  • Genetics
  • Toxicology

Background:

  • Organophosphorus (OP) compounds are linked to motor neuron disease (MND), with evidence from paraoxonase 1 polymorphisms in amyotrophic lateral sclerosis (ALS) and OP compound-induced delayed neuropathy (OPIDN).
  • OPIDN involves inhibition of neuropathy target esterase (NTE) by organophosphorylation, leading to neuropathy.
  • Previous studies suggest a connection between OP exposure, NTE inhibition, and neurodegenerative pathways.

Purpose of the Study:

  • To investigate the genetic basis of a progressive spastic paraplegia and distal muscle wasting disorder in two kindreds.
  • To determine if mutations in the neuropathy target esterase (NTE) gene are associated with this motor neuron disease.
  • To explore the role of NTE in maintaining axonal integrity and its potential contribution to other forms of MND.

Main Methods:

  • Evaluated two kindreds (one consanguineous, one nonconsanguineous) with progressive spastic paraplegia and distal muscle wasting.
  • Performed genome-wide analysis to identify linkage loci, focusing on chromosome 19p13 where NTE is mapped.
  • Conducted genetic linkage and sequence analysis of the NTE gene in affected individuals.

Main Results:

  • Genome-wide analysis identified a significant linkage locus on chromosome 19p13 in the consanguineous kindred.
  • Identified homozygous and compound heterozygous mutations in the NTE gene in affected individuals from both kindreds.
  • These disease-specific NTE mutations disrupted conserved residues in the catalytic domain or led to protein truncation.

Conclusions:

  • Mutations in the neuropathy target esterase (NTE) gene are causative of a progressive motor neuron disease.
  • NTE is crucial for maintaining axonal integrity, and its dysfunction may contribute to other neurodegenerative disorders, including ALS.
  • Abnormalities in the NTE pathway are implicated in the axonopathy observed in neuropathic OP compound exposure.

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