Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerat ion resulting in paralysis and death, usually within 3 years of onset, Path ological and animal studies implicate neurofilament involvement in ALS, but whether this is primary or secondary is not clear, The heavy neurofilament subunit (NFH) tail is composed of a repeating amino acid motif, usually X- lysine-serine-proline-Y-lysine (XKSPYK), where X is a single amino acid and Y is one to three amino acids. There are two common polymorphic variants o f 44 or 45 repeats. The tail probably regulates axonal calibre, with interf ilament spacing determined by phosphorylation of the KSP motifs, A previous study suggested an association between sporadic cases of ALS and NFH tail deletions, but two subsequent studies have found none. We have analysed sam ples from two different populations (UK 207, Scandinavia 323) with age-matc hed controls for each group (UK 219, Scandinavia 228) and have found four n ovel NFH tail deletions, each involving a whole motif, These were found in three patients with sporadic ALS and a family with autosomal dominant ALS, although another was also found in two young controls, In all cases motif d eletions were only associated with disease when paired with the long NFH al lele, The deletions all occurred within a small region of the NFH tail. Thi s has allowed us to propose a structural organization of the tail as well a s allowing observed deletions both from this study and previous reports to be organized into logical groups. These results strongly suggest that NFH m otif deletions can be a primary event in ALS but that they are not common.