N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom

Citation
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
Journal title
AMERICAN JOURNAL OF HUMAN GENETICS
ISSN journal
00029297 → ACNP
Volume
67
Issue
1
Year of publication
2000
Pages
47 - 58
Database
ISI
SICI code
0002-9297(200007)67:1<47:NDG1IM>2.0.ZU;2-B
Abstract
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.