title: Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia.
  
  
  
  We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST.
  
  
  
  We found a statistically significant linear relationship between the C9orf72 hexanucleotide bit score, a measure of genomic conservation of the aligned region across different species, and the thumb opposability index (Pearson's correlation coefficient of 0.78, p value 0.023). The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices.
  
  
  
  This may support a role of the hexanucleotide repeat in the same developmental pathways in species with higher prehensility, which may be associated with the selective vulnerability of cortico-motoneuronal cells in humans, manifested most obviously as the 'split hand' syndrome in ALS.
authors.affiliation: a Department of Basic and Clinical Neurosciences , Maurice Wohl Clinical Neuroscience Institute, King's College London , London , UK and.
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: a Department of Basic and Clinical Neurosciences , Maurice Wohl Clinical Neuroscience Institute, King's College London , London , UK and.
authors.forename: Kuang
authors.initials: K
authors.lastname: Lin
authors.affiliation: b Department of Stem Cell and Regenerative Biology , Center for Brain Science and Harvard Stem Cell Institute, Harvard University , Cambridge , MA , USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Macklis
authors.affiliation: a Department of Basic and Clinical Neurosciences , Maurice Wohl Clinical Neuroscience Institute, King's College London , London , UK and.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D000073885:C9orf72 Protein / Q000235:genetics*; D004525:Efferent Pathways / Q000473:pathology; D006071:Gorilla gorilla; D006225:Hand; D000882:Haplorhini; D009048:Motor Skills; D002679:Pan troglodytes; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D013045:Species Specificity; D013933:Thumb / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human
keywords: C9orf72; cortico-motoneuronal vulnerability; thumb opposability