Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis

Am J Hum Genet. 2012 Dec 7;91(6):1065-72. doi: 10.1016/j.ajhg.2012.09.015. Epub 2012 Nov 21.

Abstract

We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy. We thus examined the autophagy-related fate of two key autophagic proteins, SQSTM1 (p62) and MAP1LC3B (LC3), in skin fibroblasts of an affected individual, as compared to a healthy control, and found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II). siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy. Our results are strengthened by the fact that autophagy dysfunction has been implicated in a number of other neurodegenerative diseases. The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis.

Publication types

  • Case Reports
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Exons
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Genotype
  • HeLa Cells
  • Humans
  • Jews / genetics
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Neuroimaging
  • Paraparesis, Spastic / diagnosis
  • Paraparesis, Spastic / genetics*
  • Paraparesis, Spastic / metabolism
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA

Substances

  • Carrier Proteins
  • Nerve Tissue Proteins
  • TECPR2 protein, human