Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease.
In a previous study, we have shown that N-myc downstream-regulated gene 1 (NDRG1), classified in databases as a tumor suppressor and heavy metal-response protein, is mutated in hereditary motor and sensory neuropathy Lom (HMSNL), a severe autosomal recessive form of Charcot-Marie-Tooth (CMT) disease. The private founder mutation R148X, causing HMSNL in patients of Romani ethnicity, has so far remained the only molecular defect linking NDRG1 to a specific disease phenotype. Here we report the first study aiming to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded. Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. The phenotype of the IVS8-1G>A homozygote was very closely related to that of HMSNL patients. In addition, we have detected homozygosity for the known R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. No other variants were identified in the coding sequence, whereas 12 single nucleotide polymorphisms were observed in the introns. Hum Mutat 22:129-135, 2003.
Hunter
Michael
M
Laboratory of Molecular Genetics, Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, Australia.
Bernard
Rafaëlle
R
Freitas
Elizabeth
E
Boyer
Amandine
A
Morar
Bharti
B
Martins
Ian J
IJ
Tournev
Ivailo
I
Jordanova
Albena
A
Guergelcheva
Velina
V
Ishpekova
Boryana
B
Kremensky
Ivo
I
Nicholson
Garth
G
Schlotter
Beate
B
Lochmüller
Hanns
H
Voit
Thomas
T
Colomer
Jaume
J
Thomas
P K
PK
Levy
Nicolas
N
Kalaydjieva
Luba
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D022821:RNA Splice Sites; D000099259:N-myc Downstream-Regulated Gene 1 Protein