Detection of a novel frameshift mutation and regions with homozygosis within ARHGEF28 gene in familial amyotrophic lateral sclerosis

Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):444-51. doi: 10.3109/21678421.2012.758288. Epub 2013 Jan 4.


Rho guanine nucleotide exchange factor (RGNEF) is a novel NFL mRNA destabilizing factor that forms neuronal cytoplasmic inclusions in spinal motor neurons in both sporadic (SALS) and familial (FALS) ALS patients. Given the observation of genetic mutations in a number of mRNA binding proteins associated with ALS, including TDP-43, FUS/TLS and mtSOD1, we analysed the ARHGEF28 gene (approx. 316 kb) that encodes for RGNEF in FALS cases to determine if mutations were present. We performed genomic sequencing, copy number variation analysis using TaqMan real-time PCR and spinal motor neuron immunohistochemistry using a novel RGNEF antibody. In this limited sample of FALS cases (n=7) we identified a heterozygous mutation that is predicted to generate a premature truncated gene product. We also observed extensive regions of homozygosity in the ARHGEF28 gene in two FALS patients. In conclusion, our findings of genetic alterations in the ARHGEF28 gene in cases of FALS suggest that a more comprehensive genetic analysis would be warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Case-Control Studies
  • DNA Copy Number Variations
  • Female
  • Frameshift Mutation
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Real-Time Polymerase Chain Reaction
  • Spinal Cord / metabolism*


  • ARHGEF28 protein, human
  • Guanine Nucleotide Exchange Factors