ASN Neuro (Aug 2015)

Mutation Resulting in Sortilin Deficiency and p75 Upregulation in a Family With Essential Tremor

  • Elena Sánchez,
  • Alberto Bergareche,
  • Catharine E. Krebs,
  • Ana Gorostidi,
  • Vladimir Makarov,
  • Javier Ruiz-Martinez,
  • Alejo Chorny,
  • Adolfo Lopez de Munain,
  • Jose Felix Marti-Masso,
  • Coro Paisán-Ruiz

DOI
https://doi.org/10.1177/1759091415598290
Journal volume & issue
Vol. 7

Abstract

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*These authors contributed equally to this work. Essential tremor (ET) is the most prevalent movement disorder affecting millions of people in the United States. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In this study, whole exome sequencing and subsequent approaches were performed in a family with an autosomal dominant form of early-onset ET. Functional analyses including mutagenesis, cell culture, gene expression, enzyme-linked immunosorbent, and apoptosis assays were also performed. A disease-segregating mutation (p.Gly171Ala), absent in normal population, was identified in the SORT1 gene. The p.Gly171Ala mutation was shown not only to impair the expression of its encoding protein sortilin but also the mRNA levels of its binding partner p75 neurotrophin receptor that is known to be implicated in brain injury, neuronal apoptosis, and neurotransmission.