title: Loss of ERLIN2 function leads to juvenile primary lateral sclerosis.
abstract: OBJECTIVE
  Primary lateral sclerosis (PLS) is a motor neuron disorder that exclusively affects upper motor neurons leading to their degeneration. Mutations in the ALS2 gene encoding the protein Alsin have been described previously in the juvenile form of the disease. In this study, we identify mutation of the ERLIN2 gene in juvenile PLS patients and describe an in vitro model for loss of ERLIN2 function.
  
  
  METHODS
  Single nucleotide polymorphism arrays were used for homozygosity mapping. DNA sequencing of candidate genes was used to detect the underlying mutation. Level of ERLIN2 mRNA was measured by quantitative real time polymerase chain reaction. Knocking down ERLIN2 in NSC34 cells was accomplished by short-hairpin RNA interference.
  
  
  RESULTS
  We identified a splice junction mutation in the ERLIN2 gene-a component of the endoplasmic reticulum (ER) lipid rafts-that resulted in abnormal splicing of ERLIN2 transcript and nonsense-mediated decay of ERLIN2 mRNA. Knocking down ERLIN2 in NSC34 cells suppressed their growth in culture.
  
  
  CONCLUSIONS
  Recently, we found that mutation of SIGMAR1, a component of ER lipid rafts, leads to juvenile amyotrophic lateral sclerosis. The identification of mutation in another component of the ER lipid rafts in juvenile PLS patients emphasizes their role in motor neuron function. Furthermore, the discovered effect of ERLIN2 loss on cell growth may advance understanding of the mechanism behind motor neuron degeneration in PLS.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. amr@kfshrc.edu.sa
authors.forename: Amr
authors.initials: A
authors.lastname: Al-Saif
authors.forename: Saeed
authors.initials: S
authors.lastname: Bohlega
authors.forename: Futwan
authors.initials: F
authors.lastname: Al-Mohanna
mesh_terms: D000293:Adolescent; D002452:Cell Count; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000378:metabolism; D007223:Infant; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D016472:Motor Neuron Disease / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: C121703:ERLIN2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D004247:DNA; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent