L. Kalaydjieva et al., N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom, AM J HU GEN, 67(1), 2000, pp. 47-58
Citations number
54
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CM
T) disease belongs, are a common cause of disability in adulthood. Growing
awareness that axonal loss, rather than demyelination per se, is responsibl
e for the neurological deficit in demyelinating CMT disease has focused res
earch on the mechanisms of early development, cell differentiation, and cel
l-cell interactions in the peripheral nervous system. Autosomal recessive p
eripheral neuropathies are relatively rare but are clinically more severe t
han autosomal dominant forms of CMT, and understanding their molecular basi
s may provide a new perspective on these mechanisms. Here we report the ide
ntification of the gene responsible for hereditary motor and sensory neurop
athy-Lom (HMSNL). HMSNL shows features of Schwann-cell dysfunction and a co
ncomitant early axonal involvement, suggesting that impaired axonglia inter
actions play a major role in its pathogenesis. The gene was previously mapp
ed to 8q24.3, where conserved disease haplotypes suggested genetic homogene
ity and a single founder mutation. We have reduced the HMSNL interval to 20
0 kb and have characterized it by means of large-scale genomic sequencing.
Sequence analysis of two genes located in the critical region identified th
e founder HMSNL mutation: a premature-termination codon at position 148 of
the N-myc downstream-regulated gene 1 (NDRG1). NDRG1 is ubiquitously expres
sed and has been proposed to play a role in growth arrest and cell differen
tiation, possibly as a signaling protein shuttling between the cytoplasm an
d the nucleus. We have studied expression in peripheral nerve and have dete
cted particularly high levels in the Schwann cell. Taken together, these fi
ndings point to NDRG1 having a role in the peripheral nervous system, possi
bly in the Schwann-cell signaling necessary for axonal survival.