Defective mitochondrial mRNA maturation is associated with spastic ataxia

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Andrew H Crosby1, Heema Patel, Barry A Chioza

  • 1Centre for Medical Genetics, St. George's University London, UK. acrosby@sgul.ac.uk

American Journal of Human Genetics
|October 26, 2010
PubMed

Insights

A mutation in MTPAP causes spastic ataxia by truncating mitochondrial mRNA poly(A) tails, revealing a new mechanism for neurodegenerative disorders.

Area of Science:

  • Mitochondrial biology
  • Neurogenetics
  • Molecular medicine

Background:

  • Mitochondrial gene expression relies on mRNA polyadenylation by mitochondrial poly(A) RNA polymerase.
  • Defects in mitochondrial DNA maintenance cause known clinical disorders.
  • The genetic basis of some neurodegenerative diseases remains unclear.

Purpose of the Study:

  • To investigate the molecular cause of autosomal-recessive spastic ataxia with optic atrophy in the Old Order Amish.
  • To identify the genetic mutation associated with the observed disease phenotype.
  • To elucidate the role of mitochondrial mRNA maturation in human disease.

Main Methods:

  • Molecular investigation of affected individuals.
  • Mutation analysis of the MTPAP gene.
  • Poly(A) tail-length assays on mitochondrial mRNAs.

Main Results:

  • A mutation in the MTPAP gene was identified in affected individuals.
  • Mitochondrial mRNAs from patients exhibited severely truncated poly(A) tails.
  • This indicates a defect in mitochondrial mRNA maturation.

Conclusions:

  • Defective mitochondrial mRNA maturation, specifically polyadenylation, is linked to human spastic ataxia.
  • This finding expands the known mechanisms of mitochondrial disease beyond DNA maintenance.
  • Mitochondrial mRNA processing defects should be considered in complex neurodegenerative disorders.

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