Human Molecular Genetics, Vol 8, 157-164, Copyright © 1999 by Oxford University Press
A Al-Chalabi, PM Andersen, P Nilsson, B Chioza, JL Andersson, C Russ, CE Shaw, JF Powell and PN Leigh
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron
degeneration resulting in paralysis and death, usually within 3 years of
onset. Pathological 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 of 44 or 45 repeats. The tail probably regulates
axonal calibre, with interfilament 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 samples from two different populations (UK 207,
Scandinavia 323) with age-matched controls for each group (UK 219,
Scandinavia 228) and have found four novel 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 deletions were only
associated with disease when paired with the long NFH allele. The deletions
all occurred within a small region of the NFH tail. This has allowed us to
propose a structural organization of the tail as well as allowing observed
deletions both from this study and previous reports to be organized into
logical groups. These results strongly suggest that NFH motif deletions can
be a primary event in ALS but that they are not common.
ARTICLES
Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis
Departments of Neuroscience and Clinical Neurosciences, Institute of Psychiatry and King's College School of Medicine and Dentistry, London SE5 8AF, UK. ammar@iop.bpmf.ac.uk
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